Compositions and methods for delivery of hydrophobic active agents

ABSTRACT

Disclosed herein is a delivery composition for administering a hydrophobic active agent. In one embodiment, a delivery composition for local administration of a hydrophobic active agent to a tissue or organ of a patient is disclosed. In one embodiment, the delivery composition includes a cationic delivery agent, a therapeutically effective amount of a hydrophobic active agent and a pharmaceutically acceptable aqueous carrier. In one embodiment, the cationic delivery agent includes polyethyleneimine (PEI). In an embodiment, the invention includes a drug delivery device including a substrate; and coated therapeutic agent particles disposed on the substrate, the coated therapeutic agent particles comprising a particulate hydrophobic therapeutic agent; and a vinyl amine polymer. Methods of making the delivery composition, as well as kits and methods of use are also included herein.

This application is a continuation-in-part of U.S. application Ser. No.14/072,520, filed Nov. 5, 2013, which claims the benefit of U.S.Provisional Application No. 61/722,735, filed Nov. 5, 2012 and U.S.Provisional Application No. 61/740,713, filed Dec. 21, 2012. Thisapplication also claims the benefit of U.S. Provisional Application No.61/824,160, filed May 16, 2013. The contents of all of theseapplications are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for deliveringbiologically active agents to a patient. More specifically, the presentinvention relates to compositions and methods for local administrationof hydrophobic active agents to a patient, such as coated hydrophobicactive agent particles with excipients.

BACKGROUND OF THE INVENTION

Generally, the initial focus during development of a biologically activeagent is the physiochemical properties of the pharmaceutical compound,in particular the therapeutic function of the compound. Once thebiological activity of the active agent is defined, the design focustypically shifts to the systems and formulations by which the activeagent is delivered. In particular, one focus during development ofdelivery systems and formulations is the provision of a system orformulation in which therapeutic titers of the active agent are able toreach the appropriate anatomical location or compartment afteradministration.

The phrase “route of administration” refers to the path by which anactive agent is brought into contact with the body and is determinedprimarily by the properties of the active agent and by the therapeuticobjectives. The route of administration that is chosen for a particularactive agent may have a profound effect upon the speed and efficiency ofthe active agent upon administration.

In general, routes of administration can be classified by whether theeffect is local or systemic. For local delivery, an active agent isapplied directly to the tissue or organ for which treatment is sought.The effect of local delivery is limited primarily to the tissue or organto which the active agent is applied. For example, local delivery may beaccomplished through the use of compositions such as liniments, lotions,drops, ointments, creams, suppositories, emulsions, solutions,suspensions and the like. Local delivery can also be accomplished usingspecial delivery devices such as catheters, syringes or implantablesdesigned to convey drug to a specific region in the body. In contrast,an active agent administered systemically enters the blood or lymphaticsupply and may be felt some distance from the site of administration.For systemic delivery, oral and parenteral routes are typically used.

A particular example of a site of administration is the vascular system.The vascular system of the human is subject to blockage due to plaquewithin the arteries. Partial and even complete blockage of arteries bythe formation of an atherosclerotic plaque is a well-known and frequentmedical problem. Frequently, such blockage occurs in the coronaryarteries. Blockages may also occur secondary to past treatment ofspecific sites (restenosis—such as that stemming from rapidly dividingsmooth muscle cells). In addition, blockages can also occur in thecontext of peripheral arteries.

Blockages may be treated using atherectomy devices, which mechanicallyremove the plaque; hot or cold lasers, which vaporize the plaque;stents, which hold the artery open; and other devices and proceduresdesigned to increase blood flow through the artery.

One common procedure for the treatment of blocked arteries ispercutaneous transluminal coronary angioplasty (PTCA), also referred toas balloon angioplasty. In this procedure, a catheter having aninflatable balloon at its distal end is introduced into the coronaryartery, the deflated, folded balloon is positioned at the stenotic site,and then the balloon is inflated. Inflation of the balloon disrupts andflattens the plaque against the arterial wall, and stretches thearterial wall, resulting in enlargement of the intraluminal passagewayand increased blood flow. After such expansion, the balloon is deflated,and the balloon catheter removed. A similar procedure, calledpercutaneous transluminal angioplasty (PTA), is used in arteries otherthan coronary arteries in the vascular system. In other relatedprocedures, a small mesh tube, referred to as a stent is implanted atthe stenotic site to help maintain patency of the coronary artery. Inrotoblation procedures, also called percutaneous transluminal rotationalatherectomy (PCRA), a small, diamond-tipped, drill-like device isinserted into the affected artery by a catheterization procedure toremove fatty deposits or plaque. In a cutting balloon procedure, aballoon catheter with small blades is inflated to position the blades,score the plaque and compress the fatty matter into the artery wall.During one or more of these procedures, it may be desirable to deliver atherapeutic agent or drug to the area where the treatment is occurringto prevent restenosis, repair vessel dissections or small aneurysms orprovide other desired therapy.

Additionally, it may be desirable to transfer therapeutic agents toother locations in a mammal, such as the skin, neurovasculature, nasal,oral, the lungs, the mucosa, sinus, the GI tract or the renal peripheralvasculature.

SUMMARY OF THE INVENTION

Disclosed herein is a delivery composition for administration of ahydrophobic active agent, along with kits that include the deliverycompositions, methods of making the delivery composition, and methods ofusing the delivery composition. In particular the invention provides adelivery composition for local administration of a hydrophobic activeagent.

In one embodiment, the delivery composition includes a cationic deliveryagent, a therapeutically effective amount of the hydrophobic activeagent; and a pharmaceutically acceptable aqueous carrier. In oneembodiment, the hydrophobic active agent is combined with thepharmaceutically acceptable aqueous carrier to form a suspension. Inanother embodiment, the cationic delivery agent is dissolved in thepharmaceutically acceptable carrier to form a solution. In a moreparticular embodiment, the cationic delivery agent includespolyetheyleneimine (PEI), for example, dissolved PEI, more particularly,branched PEI. In one embodiment, the cationic delivery agent includesbranched PEI with a molecular weight of at least about 25 kD and up toabout 5000 kD, at least about 70 kD and up to about 4000 kD, at leastabout 100 kD and up to about 3000 kD, or at least about 500 kD and up toabout 1000 kD. In one embodiment, the branched PEI has a ratio ofprimary:secondary:tertiary amines between about 1:3:1 and about 1:1:1,or between about 1:2:1 and about 1:1:1. In one embodiment, the deliverycomposition includes cationic delivery agent:hydrophobic active agent ata ratio of at least about 1:1 and up to about 1:25, at least about 1:2and up to about 1:20, or at least about 1:5 and up to about 1:10. Inanother embodiment, the delivery composition includes at least about0.05 mg/ml, 0.1 mg/ml, 0.5 mg/ml or 1 mg/ml and up to about 25 mg/mlcationic delivery agent and at least about 5 mg/ml and up to about 125mg/ml hydrophobic active agent. In another embodiment, the aqueouscarrier includes water. In another embodiment, the delivery compositionhas a pH between 5 and 9, 6 and 8, or 7 and 8. In one embodiment, thehydrophobic active agent is an antiproliferative, analgesic,anti-inflammatory, anti-arrhythmic, anti-bacterial, anti-coagulant,anti-hypertensive, anti-muscarinic, anti-neoplastic, beta-blocker,cardiac inotropic agent, corticosteroids, lipid regulating agents,anti-anginal agents, or combinations thereof. In a more particularembodiment, the hydrophobic active agent is an antiproliferativeselected from paclitaxel, sirolimus (rapamycin), everolimus, biolimusA9, zotarolimus, tacrolimus, and pimecrolimus and mixtures thereof.

The invention also provides a method of making the deliverycompositions. In one embodiment, the method includes combining thehydrophobic active agent with a pharmaceutically acceptable aqueouscarrier to form an active agent suspension; and adding the cationicdelivery agent to the active agent suspension to form the deliverycomposition. In one embodiment, the method includes a step ofcrystallizing the hydrophobic active agent before combining thehydrophobic active agent with the aqueous carrier to form the activeagent suspension. In another embodiment, the method includes a step ofcombining the cationic delivery agent with an aqueous solution to form acationic delivery agent solution before adding the cationic deliveryagent to the active agent suspension. In one embodiment, the pH of thecationic delivery agent solution is adjusted to a pH between 5 and 9before adding the cationic delivery agent to the active agentsuspension.

In another embodiment, the method of making the delivery compositionincludes combining the hydrophobic active agent with the cationicdelivery agent to form an active agent mixture; and combining the activeagent mixture with the aqueous carrier to form the delivery composition.In one embodiment, the method includes a step of crystallizing theactive agent mixture before combining the mixture with the aqueouscarrier.

The invention also provides kits that include a therapeuticallyeffective amount of hydrophobic active agent; and cationic deliveryagent. The kit components (i.e., the hydrophobic active agent and/or thecationic delivery agent) can be included in the kit as solids or asaqueous solutions, either individually or combined. The solid kitcomponent can be either crystalline or amorphous.

In an embodiment, the invention includes a drug delivery deviceincluding a substrate, a hydrophilic polymer layer disposed on thesubstrate, and coated therapeutic agent particles disposed on thehydrophilic polymer layer. The coated therapeutic agent particles caninclude a particulate hydrophobic therapeutic agent and a vinyl aminepolymer component.

In an embodiment, the invention includes a drug delivery coatingcomprising a polymeric layer, the polymeric layer comprising ahydrophilic surface. The coating can further include coated therapeuticagent particles disposed on the hydrophilic surface, the coatedtherapeutic agent particles including a particulate hydrophobictherapeutic agent core, and a vinyl amine polymer component.

In an embodiment, the invention includes a method of forming a drugdelivery coating. The method can include applying a hydrophilic basecoat onto a substrate, forming coated therapeutic agent particles, thecoated therapeutic agent particles comprising a particulate hydrophobictherapeutic agent and a vinyl amine polymer component, and applying thecoated therapeutic agent particles to the substrate.

In an embodiment, the invention includes a medical device comprising acapsule housing; control circuitry disposed with in the capsule housing;and at least one moveable element operably connected to the capsulehousing. The moveable element can include a substrate and a coatingdisposed on the substrate, the coating comprising; a hydrophilic polymerlayer disposed on the substrate; and coated therapeutic agent particlesdisposed on the hydrophilic polymer layer, the coated therapeutic agentparticles comprising a particulate hydrophobic therapeutic agent; and avinyl amine polymer component.

In an embodiment, the invention includes a medical device including acapsule housing; control circuitry disposed with in the capsule housing;at least one moveable element operably connected to the capsule housing,the moveable element comprising a substrate and a coating disposed onthe substrate, the coating comprising a cationic delivery agent; atherapeutically effective amount of the hydrophobic active agent; and apharmaceutically acceptable aqueous carrier.

The invention also provides methods for local administration of atherapeutically or prophylactically effective amount of a hydrophobicactive agent to a tissue or organ of a patient.

BRIEF DESCRIPTION OF THE FIGURES

The invention may be more completely understood in connection with thefollowing drawings, in which:

FIG. 1 is a graph showing the amount of paclitaxel adhered and/ortransferred to different surfaces with or without seeded endothelialcells in the presence or absence of PEI.

FIG. 2 is a graph showing the amount of paclitaxel transferred toMatrigel™ surfaces with or without seeded endothelial cells in thepresence or absence of PEI.

FIG. 3 is a graph showing delivery of paclitaxel to endothelial cellsand tissues using cells grown on Matrigel™ coated cell culture plates inthe presence or absence of PEI and other excipients such as radio-opaqueiopromide.

FIG. 4 is a graph showing the amount of paclitaxel transferred toMatrigel™ surfaces in the presence of varying concentrations of heparinin the presence or absence of PEI.

FIG. 5 is a graph showing the amount of paclitaxel transferred toMatrigel™/HCAEC surfaces in the presence of varying concentrations ofheparin in the presence or absence of PEI.

FIG. 6 is a graph showing the influence of molecular weight in adhesionof paclitaxel to surfaces with or without seeded endothelial cells.

FIG. 7 is a schematic cross-sectional diagram of a coating in accordancewith an embodiment herein.

FIG. 8 is a schematic cross-sectional diagram of a coating in accordancewith an embodiment herein.

FIG. 9 is a schematic cross-sectional diagram of a coating in accordancewith an embodiment herein.

FIG. 10 is a schematic cross-sectional diagram of a coating inaccordance with an embodiment herein.

FIG. 11 is a schematic diagram of a device in accordance with anembodiment herein.

FIG. 12 is graph showing amounts of paclitaxel adsorbed to a matrigelsurface comparing the effects of different excipients.

FIG. 13 is a graph showing amounts of paclitaxel adsorbed to a matrigelsurface while varying the fractions of PVP and pNVA in a copolymer.

FIG. 14 is a graph showing the zeta potential (mV) of paclitaxelparticles while varying the fractions of PVP and pNVA in a copolymer.

FIG. 15 is a graph showing disposition of rapamycin comparing theeffects of different excipients.

FIG. 16 is a schematic view of a device in accordance with an embodimentof the invention.

FIG. 17 is a schematic view of the device shown in FIG. 16 in adifferent configuration.

FIG. 18 is a schematic view of a device in accordance with an embodimentof the invention.

FIG. 19 is a schematic view of a moveable element in accordance withvarious embodiments herein.

FIG. 20 is a schematic end view of a moveable element in accordance withvarious embodiments herein.

FIG. 21 is a schematic view of a moveable element in accordance withvarious embodiments herein.

While the invention is susceptible to various modifications andalternative forms, specifics thereof have been shown by way of exampleand drawings, and will be described in detail. It should be understood,however, that the invention is not limited to the particular embodimentsdescribed. On the contrary, the intention is to cover modifications,equivalents, and alternatives falling within the spirit and scope of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the present invention described herein are notintended to be exhaustive or to limit the invention to the precise formsdisclosed in the following detailed description. Rather, the embodimentsare chosen and described so that others skilled in the art canappreciate and understand the principles and practices of the presentinvention.

All publications and patents mentioned herein are hereby incorporated byreference. The publications and patents disclosed herein are providedsolely for their disclosure. Nothing herein is to be construed as anadmission that the inventors are not entitled to antedate anypublication and/or patent, including any publication and/or patent citedherein.

As described above, in association with procedures such as percutaneoustransluminal coronary angioplasty (PTCA), percutaneous transluminalangioplasty (PTA), and the like, it can be desirable to deliver atherapeutic agent or drug to the area where the treatment is occurringto prevent restenosis, repair vessel dissections or small aneurysms orprovide other desired therapy. One approach for accomplishing this is todeliver a therapeutic agent (or active agent) to the desired tissue siteusing a drug delivery device such as a drug eluting balloon catheter ora drug-containing balloon catheter.

Drug delivery coatings for certain medical applications desirablyexhibit various properties. By way of example, in the context of a drugeluting balloon catheter or a drug-containing balloon catheter, thecoating should maintain structural integrity during steps associatedwith preparation of the balloon catheter device include pleating,folding, and curing (such as heat treatment). In addition, it isdesirable for the coating to maintain structural integrity during theprocess of passing through the vasculature through a catheter and/orover the guide wire, with limited loss of the active agent. Yet, it isalso desirable upon inflation of the balloon at the desired site totransfer a substantial amount of the active agent from the balloon andonto the vessel wall. In addition, it is desirable to maximize uptake ofthe active agent into the tissue of the of the vessel wall and reducethe amount of active agent that is washed away into the blood flowingthrough the treatment site in the vasculature.

Embodiments herein can be useful to enhance one or more desirableproperties of drug delivery coatings, such as those properties desirablein the context of drug eluting balloon catheters, drug-containingballoon catheters and similar devices. In various embodiments, a drugdelivery device is provided that includes a substrate and coatedtherapeutic agent particles disposed on the substrate. The coatedtherapeutic agent particles can include a particulate hydrophobictherapeutic agent and a vinyl amine polymer component disposed over theparticulate hydrophobic therapeutic agent.

The invention described herein provides compositions and methods fordelivery of an active agent to a patient. The compositions are referredto herein as “delivery compositions.” As used herein, the term “route ofadministration” refers to the path by which an active agent is broughtinto contact with the body. The particular route of administration usedwith a particular active agent is determined primarily by properties ofthe active agent and by therapeutic objectives. In one embodiment, theinvention provides compositions and methods for local administration ofan active agent to a patient. As used herein, the term “localadministration” refers to a route of administration in which atherapeutically effective amount of an active agent is applied directlyto the tissue or organ for which treatment is sought, wherein thetherapeutic effect of the active agent is limited primarily to thetissue or organ to which the active agent is applied. One advantage oflocal administration of an active agent is the ability to attain apharmaceutically relevant concentration of active agent at a desiredsite, while reducing the risk of systemic toxicity. It is noted thatsome active agent may disperse from the local site of administrationduring local delivery. In general, less than about 50%, 40%, 30%, 20%,10%, 5%, 4%, 3%, 2% or 1% of the active agent disperses from the site ofadministration during local administration. In contrast, for systemicdelivery, the active agent is administered at a convenient access site,for example, intravascularly, intramuscularly, or orally and travelsthrough the blood stream to the tissues or organs for which treatment issought. In systemic delivery, more than 50% of the active agentdisperses from the site of administration during systemicadministration.

In a more particular embodiment, the invention provides compositions andmethods for local delivery of a therapeutic amount of a hydrophobicactive agent to a tissue or organ of a patient. In one embodiment, theinvention provides a composition for local delivery of a hydrophobicactive agent, wherein the composition includes the hydrophobic activeagent and a cationic delivery agent. Suitable cationic delivery agentdelivery and hydrophobic therapeutic agents are described in greaterdetail below. In another embodiment, one or more additives may beincluded in the delivery composition. Exemplary additive components aredescribed in greater detail below.

Referring now to FIG. 7, a schematic cross-sectional diagram (not toscale) is provided of a coating in accordance with an embodiment herein.In this embodiment, coated therapeutic agent particles 104 are disposedon a substrate 102. Exemplary substrates are described in greater detailbelow. The coated therapeutic agent particles 104 can include a vinylamine polymer component 108 disposed over a particulate hydrophobictherapeutic agent 106. It will be appreciated that as actually appliedthere will be many hydrophobic therapeutic agent particulates within agiven coating and that a single particulate is shown in FIG. 7 just forpurposes of ease of illustration. Exemplary vinyl amine polymercomponent compositions and hydrophobic therapeutic agents are describedin greater detail below.

In some embodiments, nucleic acids may also be included in coatingsherein. By way of example, nucleic acids, including but not limited tosiRNA, may be associated with the vinyl amine polymer. Exemplary nucleicacids are described in greater detail below. Referring now to FIG. 8, aschematic cross-sectional diagram (not to scale) is provided of anotherembodiment herein. In this embodiment, coated therapeutic agentparticles 204 are disposed on a substrate 202. The coated therapeuticagent particles 204 can include a plurality of vinyl amine polymers 208disposed over a particulate hydrophobic therapeutic agent 206. Nucleicacids 212 can be associated with the vinyl amine polymers.

In some embodiments, an additive may be included along with the coatedtherapeutic agent particles 304 in coatings herein. Referring now toFIG. 9, a schematic cross-sectional diagram (not to scale) is providedof another embodiment. In this embodiment, coated therapeutic agentparticles 304 are disposed on a substrate 302. An additive 314 can bedisposed along with the coated therapeutic agent particles 304. Theamount of the additive 314 can be more than, less than, or equal to theamount of the coated therapeutic agent particles 304. In someembodiments, the additive 314 can form a matrix or layer in which thecoated therapeutic agent particles 304 are disposed. In variousembodiments, the additive can be hydrophilic. Exemplary additivecomponents are described in greater detail below. The coated therapeuticagent particles 304 can include a plurality of vinyl amine polymers 308disposed over a particulate hydrophobic therapeutic agent 306.

In some embodiments, a hydrophilic polymer layer can be disposed on thesurface of the substrate, between the coated therapeutic agent particlesand the surface of the substrate. Exemplary polymers for the hydrophilicpolymer layer are described in greater detail below. Referring now toFIG. 10, a schematic cross-sectional diagram (not to scale) is providedof another embodiment herein. In this embodiment, coated therapeuticagent particles 404 are disposed on a hydrophilic polymer layer 416,which is in turn disposed on a substrate 402. The coated therapeuticagent particles 404 can include a plurality of vinyl amine polymers 408disposed over a particulate hydrophobic therapeutic agent 406.

Referring now to FIG. 11, a schematic view of an exemplary device isshown in accordance with an embodiment. The device 500 can be, forexample, an angioplasty balloon catheter or a drug eluting ballooncatheter or a drug-containing balloon catheter. However, furtherexamples of exemplary devices are described in greater detail below. Thedevice 500 includes a catheter shaft 502 and a manifold end 505. Thedevice 500 also includes an inflatable balloon 504 disposed around thecatheter shaft 502. In FIG. 11, the balloon 504 is shown in an inflatedconfiguration. The catheter shaft 502 can include a channel to conveyfluid through the catheter shaft 502 and to or from the balloon 504, sothat the balloon 504 can selectively go from a deflated configuration tothe inflated configuration and back again.

The manufacture of expandable balloons is well known in the art, and anysuitable process can be carried out to provide the expandable substrateportion of the insertable medical device as described herein. Catheterballoon construction is described in various references, for example,U.S. Pat. Nos. 4,490,421, 5,556,383, 6,210,364, 6,168,748, 6,328,710,and 6,482,348. Molding processes are typically performed for balloonconstruction. In an exemplary molding process, an extruded polymerictube is radially and axially expanded at elevated temperatures within amold having the desired shape of the balloon. The balloon can besubjected to additional treatments following the molding process. Forexample, the formed balloon can be subjected to additional heating stepsto reduce shrinkage of the balloon.

Referring back to FIG. 11, the insertable medical device 500 can alsohave one or more non-expandable (or inelastic) portions. For example, ina balloon catheter, the catheter shaft 502 portion can be thenon-expandable portion. The non-expandable portion can be partially orentirely fabricated from a polymer. Polymers include those formed ofsynthetic polymers, including oligomers, homopolymers, and copolymersresulting from either addition or condensation polymerizations. Examplesof suitable addition polymers include, but are not limited to, acrylicssuch as those polymerized from methyl acrylate, methyl methacrylate,hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid,methacrylic acid, glyceryl acrylate, glyceryl methacrylate,methacrylamide, and acrylamide; vinyls such as ethylene, propylene,vinyl chloride, vinyl acetate, vinyl pyrrolidone, vinylidene difluoride,and styrene. Examples of condensation polymers include, but are notlimited to, polyamides such as polycaprolactam, polylauryl lactam,polyhexamethylene adipamide, and polyhexamethylene dodecanediamide, andalso polyurethanes, polycarbonates, polyamides, polysulfones,poly(ethylene terephthalate), polydimethylsiloxanes, andpolyetherketone. The non-expandable portion can also be partially orentirely fabricated from a metal.

Hydrophobic Active Agents

In one embodiment, the delivery composition includes one or morehydrophobic active agents. In general, the term “hydrophobic activeagent” refers to an active agent having solubility in water of less thanabout 100 μg/mL at 25° C. and neutral pH, less than about 10 μg/mL at25° C. and neutral pH, or less than about 5 μg/ml at 25° C. and neutralpH. In one embodiment, the hydrophobic active agent is crystalline. Ingeneral, the term “crystalline” refers to a thermodynamically stablesolid form of an active agent having “long range molecular order” inwhich the molecules are packed in a regularly ordered, repeatingpattern. In another embodiment, the hydrophobic active agent isamorphous. The term “amorphous” refers to a solid form of an activeagent in which the molecules do not have “long range molecular order”,but rather are randomly arranged or retain only a “short range molecularorder” typical of liquids. In general, crystalline forms of an activeagent tend to have a higher level of purity and more stability thanamorphous forms of the same active agent. Additionally, the crystallineform of an active agent tends to be more soluble than the amorphousform. One of skill in the art is aware of methods for determiningwhether an active agent is in a crystalline or amorphous form, forexample, using x-ray diffraction.

The amount of hydrophobic active agent included in the deliverycomposition can vary depending upon many factors including the desiredtherapeutic outcome. However, the composition of the invention caninclude at least about 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, or10 mg/ml, 15 mg/ml, 20 mg/ml, or 25 mg/ml or up to about 25 mg/ml, 50mg/ml, 75 mg/ml, 100 mg/ml, 125 mg/ml or 150 mg/ml hydrophobic activeagent.

It will be appreciated that hydrophobic active agents can include agentshaving many different types of activities. In some embodiments,hydrophobic active agents can include, but are not limited to,antiproliferatives such as paclitaxel, sirolimus (rapamycin),everolimus, biolimus A9, zotarolimus, tacrolimus, and pimecrolimus andmixtures thereof; analgesics and anti-inflammatory agents such asaloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac,fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen, indomethacin,ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen,oxyphenbutazone, phenylbutazone, piroxicam, sulindac; anti-arrhythmicagents such as amiodarone HCl, disopyramide, flecamide acetate,quinidine sulphate; anti-bacterial agents such as benethaminepenicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine,cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide,imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin,sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide,sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine,tetracycline, trimethoprim; anti-coagulants such as dicoumarol,dipyridamole, nicoumalone, phenindione; anti-hypertensive agents such asamlodipine, benidipine, darodipine, dilitazem HCl, diazoxide,felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine HCl,nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCL, reserpine,terazosin HCL; anti-muscarinic agents: atropine, benzhexyl HCl,biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide,oxyphencylcimine HCl, tropicamide; anti-neoplastic agents andimmunosuppressants such as aminoglutethimide, amsacrine, azathioprine,busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine,etoposide, lomustine, melphalan, mercaptopurine, methotrexate,mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate,testolactone; beta-blockers such as acebutolol, alprenolol, atenolol,labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol;cardiac inotropic agents such as aminone, digitoxin, digoxin, enoximone,lanatoside C, medigoxin; corticosteroids such as beclomethasone,betamethasone, budesonide, cortisone acetate, desoxymethasone,dexamethasone, fludrocortisone acetate, flunisolide, flucortolone,fluticasone propionate, hydrocortisone, methylprednisolone,prednisolone, prednisone, triamcinolone; lipid regulating agents such asbezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol; nitratesand other anti-anginal agents such as amyl nitrate, glyceryl trinitrate,isosorbide dinitrate, isosorbide mononitrate, pentaerythritoltetranitrate.

Other hydrophobic active agents include, but are not limited to, activeagents for treatment of hypertension (HTN), such as guanethidine.

In a particular embodiment, the hydrophobic active agent includespaclitaxel, sirolimus (rapamycin), everolimus, biolimus A9, zotarolimus,tacrolimus, and pimecrolimus and mixtures thereof.

In one embodiment, the hydrophobic active agent includeschemotherapeutics, exemplified by the family of fluorouracils (e.g. 4-FUand 5-FU) and Carmustine (bis-chloroethylnitrosourea; BCNU).

In one embodiment, the hydrophobic active agent is combined with acationic delivery agent in solution. In another embodiment, solidhydrophobic active agent, amorphous or crystalline, is combined withpure or neat cationic delivery agent, amorphous or crystalline, to forma mixture. In other embodiments, the hydrophobic active agents isconjugated to a cationic delivery agent. The conjugation can include ahydrophobic active agent covalently bonded to the cationic deliveryagent. In some embodiments wherein the hydrophobic agent is conjugatedto the cationic delivery agent a linking agent can be used to attach thehydrophobic agent to the cationic delivery agent. Suitable linkingagents include, but are not limited to, polyethylene glycol,polyethylene oxide and polypeptides of naturally-occurring andnon-naturally occurring amino acids. In some embodiments, linking agentscan be biodegradable or cleavable in vivo to assist in release of thehydrophobic active agents. Exemplary linking agents can further includealkane or aromatic compounds with heteroatom-substitutions such as N, S,Si, Se or O.

In some embodiments, the particulate hydrophobic therapeutic agent canhave an average diameter (“dn”, number average) that is less than about10 μm. Also, in some embodiments, the particulate hydrophobictherapeutic agent can have an average diameter of about 100 nm orlarger. For example, the microparticulates associated with theexpandable elastic portion can have an average diameter in the range ofabout 100 nm to about 10 μm, about 150 nm to about 2 μm, about 200 nm toabout 5 μm, or even about 0.3 μm to about 1 μm.

Vinyl Amine Polymer Component

Embodiments herein can include a vinyl amine polymer component. By wayof example, the vinyl amine polymer component can include poly(N-vinylamine) (pNVA). In some embodiments, the vinyl amine polymer componentcan include the hydrolysis products of N-vinyl formamide (pNVF). ThepNVF can be hydrolyzed to various degrees. In various embodiments, thepNVF can be at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95percent hydrolyzed. In some embodiments, the pNVF can be 100% hydrolyzedto PNVA.

It will be appreciated that the vinyl amine polymer component inaccordance with embodiments herein can also include copolymers,terpolymers, and the like including N-vinyl amine and/or N-vinylformamide subunits. In some embodiments, the vinyl amine polymercomponent can include a copolymer having the formula A-B, whereinsubunit A is N-vinyl amine and subunit B is N-vinyl formamide.Alternatively, subunit B can be an accessory subunit, such as1-vinyl-2-pyrrolidone. Further examples of accessory subunits aredescribed in greater detail below. The relative amounts of the subunitscan vary. In some embodiments, the mole percent amount of subunit A canbe at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 100 percentwith the balance comprising subunit B. In some embodiments, the vinylamine polymer component can include a copolymer having Formula I,wherein x is from 1 to 100 mole percent, and y is from 0 to 99 molepercent.

In some embodiments, the vinyl amine polymer component can include aterpolymer having the formula A-B-C, wherein subunit A is N-vinyl amine,subunit B is N-vinyl formamide, and subunit C is an accessory subunit.In some embodiments, the mole percent amount of subunit A can be atleast about 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 100 percent withthe balance comprising subunits B and/or C. In some embodiments, thevinyl amine polymer can include a terpolymer having Formula II, whereinx is from 1 to 100 mole percent, y is from 0 to 99 mole percent, and zis from 0 to 99 mole percent.

Accessory subunits can include, but are not limited to, vinyl esters,(meth)acrylate esters, vinyl imidazoles, vinyl pyridines, vinylalcohols, vinyl halides, acrylonitriles, acrylamides, vinyl silanes,styrenes, and the like. In some embodiments, the accessory subunit canbe 1-vinyl-2-pyrrolidone.

In some embodiments, the vinyl amine polymer component can includeblends of poly(N-vinyl amine) and poly(N-vinyl formamide). In someembodiments, the vinyl amine polymer component can include blends ofpoly(N-vinyl amine), poly(N-vinyl formamide), and other polymers such aspolymers of the accessory subunits referred to above.

It will be appreciated that the vinyl amine polymer component along withany additive components and other components such as solvents and thelike can have a particular pH. In some embodiments, the pH can be fromabout 2 to about 11. The pH range can include 2, 3, 4, 5, 6, 7, 8, 9,10, or 11, wherein any of those numbers can serve as the bottom or topbound of a range. In particular embodiments the pH can be from about 2to about 5. In some embodiments, the pH can be from about 3 to about 4.In some embodiments, the pH can be from about 4 to about 8. In someembodiments, the pH can be from about 5 to about 7.

Cationic Delivery Agents

In one embodiment, the delivery composition includes a hydrophobicactive agent and cationic delivery agent. While not wishing to be boundby theory, it is believed that the charge provided by the cationicdelivery agents results in the composition being electrostaticallyattracted to negative charges and/or polar groups associated with thelipid bilayer present on or in a tissues or organs of a patient orcharged/polar groups associated with the extracellular matrix (e.g,collagen, fibronectin, laminin, etc.). Consequently, combining an activeagent, particularly a hydrophobic active agent with a cationic deliveryagent in a composition for local administration helps retain thehydrophobic active agent near the site of administration. It is alsothought that the cationic delivery agent may increase tissuepermeability, thereby enhancing uptake of the active agent by the targettissue and/or organ.

In general, the upper limit for the amount of cationic delivery agentthat is included in the delivery composition is guided by the toxicitylimit for the given cationic delivery agent or the solubility of thecationic delivery agent in the aqueous carrier used in the composition.However, in one embodiment, the ratio of cationic deliveryagent:hydrophobic active agent can be up to 1:1. The lower limit for theamount of cationic delivery agent that is included in the composition isguided by the efficacy of the composition. In general, the inventorshave found that a ratio of cationic delivery agent:hydrophobic activeagent of 1:50 has limited efficacy. Consequently, the compositiongenerally has a ratio of cationic delivery agent:hydrophobic activeagent of at least 1:25. In one embodiment, the ratio of cationicdelivery agent:hydrophobic active agent is between about 1:1 and about1:25. In another embodiment, the ratio of cationic deliveryagent:hydrophobic active agent is at least about 1:2, 1:5 or 1:10 and upto about 1:10, 1:15, 1:20 or 1:25. In one embodiment, the composition ofthe invention includes at least about 0.1 mg/ml, 0.5 mg/ml, 1 mg/ml, 2mg/ml, 3 mg/ml, 4 mg/ml, or 5 mg/ml and up to about 5 mg/ml, 10 mg/ml,15 mg/ml, 20 mg/ml or 25 mg/ml cationic delivery agent.

Cationic delivery agents used in embodiments herein include compoundscontaining a portion having a positive charge in aqueous solution atneutral pH along with a portion that can exhibit affinity forhydrophobic surfaces (such as hydrophobic or amphiphilic properties) andcan therefore interface with hydrophobic active agents. In someembodiments, cationic delivery agents used in embodiments herein caninclude those having the general formula X-Y, wherein X is a positivelycharged group in aqueous solution at neutral pH and Y is a moietyexhibiting hydrophobic properties. In some embodiments, the cationicdelivery agent can include a hydrophilic head and a hydrophobic tail,along with one or more positively charged groups, typically in the areaof the hydrophilic head.

Cationic delivery agents can specifically include cationic lipids andnet neutral lipids that have a cationic group. Exemplary lipids caninclude, but are not limited to,3β-[N—(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride(DC-cholesterol); 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP);dimethyldioctadecylammonium (DDAB);1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EPC);1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA);1,2-di-(9Z-octadecenoyl)-3-dimethylammonium-propane (DODAP);1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA) and derivativesthereof. Additional lipids can include, but are not limited to,1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE); cholesterol;1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (DSPC);1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE).

Cationic delivery agents can specifically include cationic polymers.Cationic delivery agents can also include polycation-containingcyclodextrin, histones, protamines, cationized human serum albumin,aminopolysaccharides such as chitosan, peptides such as poly-L-lysine,poly-L-ornithine, and poly(4-hydroxy-L-proline ester, and polyaminessuch as polyethylenimine (PEI; available from Sigma Aldrich),polypropylenimine, polyamidoamine dendrimers (PAMAM; available fromSigma Aldrich), cationic polyoxazoline and poly(beta-aminoesters).Cationic delivery agents can also specifically include cationiclipidoids (as described by K. T. Love in the publication PNAS 107,1864-1869 (2010)). Other exemplary cationic polymers include, but arenot limited to, block copolymers such as PEG-PEI and PLGA-PEIcopolymers.

In one embodiment, the cationic delivery agent includespolyethyleneimine (PEI). PEI is a basic cationic aliphatic polymer whichcan be linear or branched. Linear PEI is a solid at room temperature andincludes predominantly secondary amines. Branched PEIs are liquid atroom temperature and include primary, secondary and tertiary aminogroups. The ratio of primary:secondary:tertiary amino groups reflectsthe amount of branching, wherein the relative amount of secondary aminogroups decreases as the amount of branching increases. In oneembodiment, PEI includes primary:secondary:tertiary amino groups at aratio of between about 1:3:1 and 1:1:1, or between about 1:2:1 and1:1:1. In another embodiment, PEI includes primary:secondary:tertiaryamino groups at a ratio of between about 1:2:1 and 1:1:1, 1:1.1:1,1:1.2:1, 1:1.3:1, 1:1.4:1, 1:1.5:1, 1:1.6:1, 1:1.7:1, 1:1.8:1, or1:1.9:1. In another embodiment, PEI is linear and includes predominantlysecondary amines. In one embodiment, branched PEI includes no more thanabout 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% secondaryamine groups. In other embodiments, PEI includes one or more quaternaryamine groups.

In one method, PEI is synthesized from monomers that include athree-membered ring in which two corners of the molecule have (—CH₂—)linkages and the third corner includes a secondary amine group (═NH). Inthe presence of a catalyst the three-membered ring is converted into ahighly branched polymer with about 25% primary amine groups, 50%secondary amine groups, and 25% tertiary amine groups. The branchedpolymers can be copolymerized to produce PEI having a variety ofmolecular weights, from 2 kD up to 5000 kD. In one embodiment, PEI has amolecular weight of at least about 25 kD, 50 kD, 70 kD, 75 kD, 100 kD,150 kD, 200 kD, 250 kD, 300 kD, 350 kD, 400 kD, 450 kD, 500 kD, 550 kD,600 kD, 650 kD, 700 kD, 750 kD, 800 kD, 850 kD, 900 kD, 950 kD or 1000kD and up to about 1000 kD, 1500 kD, 2000 kD, 2500 kD, 3000 kD, 3500 kD,4000 kD, 4500 kD or 5000 kD. Methods for synthesizing linear PEI arealso known.

The inventors have found that linear PEI is not as effective as acationic delivery agent for hydrophobic active agents when compared tobranched PEI. This could be because linear PEI is less soluble inaqueous carriers, such as water, than branched PEI. In general, linearPEI is only soluble in aqueous solutions such as water when it is heatedto a temperature of at least about 50° C. Branched PEI is generallysoluble in aqueous carriers such as water and a 5% aqueous solution ofPEI typically has a pH between about 10 and 12. As the pH of a solutionor suspension containing PEI is changed, the nature of the PEI moleculealso changes. In particular, when the pH of a solution or suspension ofPEI is between about 5 and about 9, the stability of the solution can beimproved. The pH of a PEI solution can be adjusted by titrating with anacid, such as hydrochloric acid (HCl) having a concentration betweenabout 1M and about 10 M. Advantageously, a solution with a pH betweenabout 5 and about 9 is well suited for use in vivo. Branched PEI ishighly soluble or miscible in water. The solubility limit for branchedPEI depends on the amount of branching and molecular weight. In oneembodiment, branched PEI has a solubility of at least about 0.01 mg/ml,0.1 mg/ml, 1 mg/ml, 5 mg/ml, 10 mg/ml, 25 mg/ml or 50 mg/ml, and up toabout 25 mg/ml, 50 mg/ml, 75 mg/ml, 100 mg/ml, 150 mg/ml or 200 mg/ml atroom temperature (i.e., between about 20° C. and about 25° C.).Generally, PEI is used as a cationic delivery agent in an aqueoussolution having a concentration of at least about 0.1 μg/ml, 0.2 μg/ml,0.3 μg/ml, 0.4 μg/ml, 0.5 μg/ml, and up to about 0.6 μg/ml, 0.7 μg/ml,0.8 μg/ml, 0.9 μg/ml or 1 μg/ml, wherein the aqueous solution isbuffered to a pH of at least about 5, 6 or 7 or up to about 7, 8 or 9.

In other embodiments of the present disclosure, cationic delivery agentshaving a positive charge in aqueous solutions at neutral pH include thefollowing Compounds (A-I):

Additionally, other cationic delivery agents include structures of thegeneral Formula I:

TABLE 1 Values for Variables x + z, y and R for Compounds J-R of FormulaI. Compound x + z y R Compound J 6 12.5 C₁₂H₂₅ Compound K 1.2 2 C₁₂H₂₅Compound L 6 39 C₁₂H₂₅ Compound M 6 12.5 C₁₄H₂₉ Compound N 1.2 2 C₁₄H₂₉Compound O 6 39 C₁₄H₂₉ Compound P 6 12.5 C₁₆H₃₃ Compound Q 1.2 2 C₁₆H₃₃Compound R 6 39 C₁₆H₃₃

Methods for making cationic delivery agents, such as those listed above,are described in more detail in U.S. patent application Ser. No.13/469,844, entitled “DELIVERY OF COATED HYDROPHOBIC ACTIVE AGENTPARTICLES,” the disclosure of which is hereby incorporated by referenceherein in its entirety. In general, cationic delivery agents, such asthose listed above, can generally be prepared by the reaction of anappropriate hydrophobic epoxide (e.g. oleyl epoxide) with amultifunctional amine (e.g. propylene diamine). Details of the synthesisof related cationic delivery agents are described by K. T. Love in thepublication PNAS 107, 1864-1869 (2010) and Ghonaim et al., Pharma Res27, 17-29 (2010).

It will be appreciated that polyamide derivatives of PEI (PEI-amides)can also be applied as cationic delivery agents. PEI-amides cangenerally be prepared by reacting PEI with an acid or acid derivativesuch as an acid chloride or an ester to form various PEI-amides. Forexample, PEI can be reacted with methyl oleate to form PEI-amides.

In yet other embodiments cationic delivery agents can include moietiesused to condense nucleic acids (for example lipids, peptides and othercationic polymers). In some instances these cationic delivery agents canbe used to form lipoplexes and polyplexes.

Additive Components

Additive components can be included with various embodiments herein. Insome embodiments of the present disclosure the additive components canbe hydrophilic in nature. Exemplary hydrophilic polymers include, butare not limited to, PEG, PVP and PVA.

Exemplary additive components can include saccharides. Saccharides caninclude monosaccharides, disaccharides, trisaccharides,oligosaccharides, and polysaccharides. Polysaccharides can be linear orbranched polysaccharides. Exemplary saccharides can include but are notlimited to dextrose, sucrose, maltose, mannose, trehalose, and the like.Exemplary saccharides can further include, but are not limited to,polysaccharides including pentose, and/or hexose subunits, specificallyincluding glucans such as glycogen and amylopectin, and dextrinsincluding maltodextrins, fructose, mannose, galactose, and the like.Polysaccharides can also include gums such as pullulan, arabinose,galactan, etc.

Saccharides can also include derivatives of polysaccharides. It will beappreciated that polysaccharides include a variety of functional groupsthat can serve as attachment points or can otherwise be chemicallymodified in order to alter characteristics of the saccharide. As justone example, it will be appreciated that saccharide backbones generallyinclude substantial numbers of hydroxyl groups that can be utilized toderivatize the saccharide.

Saccharides can also include copolymers and/or terpolymers, and thelike, that include saccharide and/or saccharide subunits and/or blocks.

Polysaccharides used with embodiments herein can have various molecularweights. By way of example, glycogen used with embodiments herein canhave a molecular weight of greater than about 250,000. In someembodiments glycogen used with embodiments herein can have a molecularweight of between about 100,000 and 10,000,000 Daltons.

Refinement of the molecular weight of polysaccharides can be carried outusing diafiltration. Diafiltration of polysaccharides such asmaltodextrin can be carried out using ultrafiltration membranes withdifferent pore sizes. As an example, use of one or more cassettes withmolecular weight cut-off membranes in the range of about 1K to about 500K can be used in a diafiltration process to provide polysaccharidepreparations with average molecular weights in the range of less than500 kDa, in the range of about 100 kDa to about 500 kDa, in the range ofabout 5 kDa to about 30 kDa, in the range of about 30 kDa to about 100kDa, in the range of about 10 kDa to about 30 kDa, or in the range ofabout 1 kDa to about 10 kDa.

It will be appreciated that polysaccharides such as maltodextrin andamylose of various molecular weights are commercially available from anumber of different sources. For example, Glucidex™ 6 (avg. molecularweight ˜95,000 Da) and Glucidex™ 2 (avg. molecular weight ˜300,000 Da)are available from Roquette (France); and MALTRIN™ maltodextrins ofvarious molecular weights, including molecular weights from about 12,000Da to 15,000 Da are available from GPC (Muscatine, Iowa). Examples ofother hydrophobic polysaccharide derivatives are disclosed in US PatentPublication 2007/0260054 (Chudzik), which is incorporated herein byreference.

Exemplary additive components can include amphiphilic compounds.Amphiphilic compounds include those having a relatively hydrophobicportion and a relatively hydrophilic portion. Exemplary amphiphiliccompounds can include, but are not limited to, polymers including, atleast blocks of, polyvinylpyrrolidone, polyvinyl alcohol, polyethyleneglycol, polyoxazolines (such as poly(2-alkyloxazoline) and derivatives)and the like. Exemplary amphiphilic compounds can specifically includepoloxamers. Poloxamers are nonionic triblock copolymers composed of acentral hydrophobic chain of polyoxypropylene flanked by two hydrophilicchains of polyoxyethylene. Poloxamers are frequently referred to by thetrade name PLURONIC®. It will be appreciated that many aspects of thecopolymer can be varied such the characteristics can be customized. Oneexemplary poloxamer is PLURONIC® F68 (non-ionic, co-polymer of ethyleneand propylene oxide commercially available from BASF Corporation; alsodesignated as F68 and poloxamer F68), which refers to a poloxamer havinga solid form at room temperature, a polyoxypropylene molecular mass ofapproximately 1,800 g/mol and roughly 80% polyoxyethylene content, witha total molecular weight of approximately 8,400 g/mol, the copolymerterminating in primary hydroxyl groups.

In other embodiments, the delivery composition of the invention caninclude one or more additional components, such as a diluent, excipient,adjuvant, emulsifier, buffer, stabilizer, preservative, and the like. Inone embodiment, the delivery composition includes one or more contrastagents, for example, an iodinated radiocontrast agent.

In another embodiment, the delivery composition of the invention caninclude one or more agents that enhance tissue penetration, including,but not limited to zonulin, propylene glycol, mono-, di- ortri-glycerides etc.

Exemplary additive components can further include compounds thatstabilize poorly water soluble pharmaceutical agents. Exemplary additivecomponents providing such stabilization include biocompatible polymers,for example albumins. Additional additive components are described inU.S. Pat. No. 7,034,765 (De et al.), the disclosure of which isincorporated herein by reference. Stabilization of suspensions andemulsions can also be provided by compounds, for example, such assurfactants (e.g. F68).

Nucleic Acids

Nucleic acids used with embodiments of the invention can include varioustypes of nucleic acids that can function to provide a therapeuticeffect. Exemplary types of nucleic acids can include, but are notlimited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), smallinterfering RNA (siRNA), micro RNA (miRNA), piwi-interacting RNA(piRNA), short hairpin RNA (shRNA), antisense nucleic acids, aptamers,ribozymes, locked nucleic acids and catalytic DNA. In a particularembodiment, the nucleic acid used is siRNA and/or derivatives thereof.

Hydrophilic Base Coatings

In various embodiments, a hydrophilic base coating is included. Oneclass of hydrophilic polymers useful as polymeric materials forhydrophilic base coat formation is synthetic hydrophilic polymers.Synthetic hydrophilic polymers that are biostable (i.e., that show noappreciable degradation in vivo) can be prepared from any suitablemonomer including acrylic monomers, vinyl monomers, ether monomers, orcombinations of any one or more of these types of monomers. Acrylicmonomers include, for example, methacrylate, methyl methacrylate,hydroxyethyl methacrylate, hydroxyethyl acrylate, methacrylic acid,acrylic acid, glycerol acrylate, glycerol methacrylate, acrylamide,methacrylamide, dimethylacrylamide (DMA), and derivatives and/ormixtures of any of these. Vinyl monomers include, for example, vinylacetate, vinylpyrrolidone, vinyl alcohol, and derivatives of any ofthese. Ether monomers include, for example, ethylene oxide, propyleneoxide, butylene oxide, and derivatives of any of these. Examples ofpolymers that can be formed from these monomers includepoly(acrylamide), poly(methacrylamide), poly(vinylpyrrolidone),poly(acrylic acid), poly(ethylene glycol), poly(vinyl alcohol), andpoly(HEMA). Examples of hydrophilic copolymers include, for example,methyl vinyl ether/maleic anhydride copolymers and vinylpyrrolidone/(meth)acrylamide copolymers. Mixtures of homopolymers and/orcopolymers can be used.

Examples of some acrylamide-based polymers, such aspoly(N,Ndimethylacrylamide-co-aminopropylmethacrylamide) andpoly(acrylamide-co-N,Ndimethylaminopropylmethacrylamide) are describedin example 2 of U.S. Pat. No. 7,807,750 (Taton et al.), the disclosureof which is incorporated herein by reference.

In some embodiments, the hydrophilic polymer is a vinyl pyrrolidonepolymer, or a vinyl pyrrolidone/(meth)acrylamide copolymer such aspoly(vinylpyrrolidone-comethacrylamide). If a PVP copolymer is used, itcan be a copolymer of vinylpyrrolidone and a monomer selected from thegroup of acrylamide monomers. Exemplary acrylamide monomers include(meth)acrylamide and (meth)acrylamide derivatives, such asalkyl(meth)acrylamide, as exemplified by dimethylacrylamide, andaminoalkyl(meth)acrylamide, as exemplified by aminopropylmethacrylamideand dimethylaminopropylmethacrylamide. For example,poly(vinylpyrrolidone-co-N,N dimethylaminopropylmethacrylamide) isdescribed in example 2 of U.S. Pat. No. 7,807,750 (Taton et al.).

In one embodiment, the polymers and copolymers as described arederivatized with one or more photoactivatable group(s). Exemplaryphotoreactive groups that can be pendent from biostable hydrophilicpolymer include aryl ketones, such as acetophenone, benzophenone,anthraquinone, anthrone, quinone, and anthrone-like heterocycles. Thisprovides a hydrophilic polymer having a pendent activatable photogroupthat can be applied to the expandable and collapsible structure, andthen treated with actinic radiation sufficient to activate thephotogroups and cause covalent bonding to a target, such as the materialof the expandable and collapsible structure. Use of photo-hydrophilicpolymers can be used to provide a durable coating of a flexible hydrogelmatrix, with the hydrophilic polymeric materials covalently bonded tothe material of the expandable and collapsible structure.

A hydrophilic polymer having pendent photoreactive groups can be used toprepare the flexible hydrogel coating. Methods of preparing hydrophilicpolymers having photoreactive groups are known in the art. For example,methods for the preparation of photo-PVP are described in U.S. Pat. No.5,414,075, the disclosure of which is incorporated herein by reference.Methods for the preparation of photo-polyacrylamide are described inU.S. Pat. No. 6,007,833, the disclosure of which is incorporated hereinby reference.

In another embodiment, the polymers and copolymers as described arederivatized with one or more polymerizable group(s). Polymers withpendent polymerizable groups are commonly referred to macromers. Thepolymerizable group(s) can be present at the terminal portions (ends) ofthe polymeric strand or can be present along the length of the polymer.In one embodiment polymerizable groups are located randomly along thelength of the polymer.

Optionally, the coating can include a cross-linking agent. Acrosslinking agent can promote the association of polymers in thecoating, or the bonding of polymers to the coated surface. The choice ofa particular crosslinking agent can depend on the ingredients of thecoating composition.

Suitable crosslinking agents include two or more activatable groups,which can react with the polymers in the composition. Suitableactivatable groups include photoreactive groups as described herein,like aryl ketones, such as acetophenone, benzophenone, anthraquinone,anthrone, quinone, and anthrone-like heterocycles. The photoactivatablecross-linking agent can be ionic, and can have good solubility in anaqueous composition. Thus, in some embodiments, at least one ionicphotoactivatable cross-linking agent is used to form the coating. Theionic cross-linking agent can include an acidic group or salt thereof,such as selected from sulfonic acids, carboxylic acids, phosphonicacids, salts thereof, and the like. Exemplary counter ions includealkali, alkaline earths metals, ammonium, protonated amines, and thelike.

Exemplary ionic photoactivatable cross-linking agents include4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid or salt;2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid or salt;2,5-bis(4-benzoylmethyleneoxy)benzene-1-sulfonic acid or salt;N,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid or salt,and the like. See U.S. Pat. No. 6,077,698 (Swan et al.), U.S. Pat. No.6,278,018 (Swan), U.S. Pat. No. 6,603,040 (Swan) and U.S. Pat. No.7,138,541 (Swan) the disclosures of which are incorporated herein byreference.

Other exemplary ionic photoactivatable cross-linking agents includeethylenebis(4-benzoylbenzyldimethylammonium) dibromide andhexamethylenebis(4-benzoylbenzyldimethylammonium) dibromide and thelike. See U.S. Pat. No. 5,714,360 (Swan et al.) the disclosures of whichare incorporated herein by reference.

In yet other embodiments, restrained multifunctional reagents withphotoactivable cross-linking groups can be used. In some examples theserestrained multifunctional reagents include tetrakis (4-benzoylbenzylether) of pentaerthyritol and the tetrakis (4-benzoylbenzoate ester) ofpentaerthyritol. See U.S. Pat. No. 5,414,075 (Swan et al.) and U.S. Pat.No. 5,637,460 (Swan et al.) the disclosures of which are incorporatedherein by reference.

Additional cross-linking agents can include those having formulaPhoto¹-LG-Photo², wherein Photo¹ and Photo² independently represent atleast one photoreactive group and LG represents a linking groupcomprising at least one silicon or at least one phosphorus atom, whereinthe degradable linking agent comprises a covalent linkage between atleast one photoreactive group and the linking group, wherein thecovalent linkage between at least one photoreactive group and thelinking group is interrupted by at least one heteroatom. See U.S. Publ.Pat. App. No. 2011/0245367 (Kurdyumov, et al.), the disclosure of whichis incorporated herein by reference. Further cross-linking agents caninclude those having a core molecule with one or more charged groups andone or more photoreactive groups covalently attached to the coremolecule by one or more degradable linkers. See U.S. Publ. Pat. App. No.2011/0144373 (Swan, et al.), the disclosure of which is incorporatedherein by reference.

Natural polymers can also be used to form the hydrophilic base coat.Natural polymers include polysaccharides, for example, polydextrans,carboxymethylcellulose, and hydroxymethylcellulose; glycosaminoglycans,for example, hyaluronic acid; polypeptides, for example, solubleproteins such as collagen, albumin, and avidin; and combinations ofthese natural polymers. Combinations of natural and synthetic polymerscan also be used.

Substrates

The substrate can be formed from any desirable material, or combinationof materials, suitable for use within the body. In some embodiments thesubstrate is formed from compliant and flexible materials, such aselastomers (polymers with elastic properties). Exemplary elastomers canbe formed from various polymers including polyurethanes and polyurethanecopolymers, polyethylene, styrene-butadiene copolymers, polyisoprene,isobutylene-isoprene copolymers (butyl rubber), including halogenatedbutyl rubber, butadiene-styrene-acrylonitrile copolymers, siliconepolymers, fluorosilicone polymers, polycarbonates, polyamides,polyesters, polyvinyl chloride, polyether-polyester copolymers,polyether-polyamide copolymers, and the like. The substrate can be madeof a single elastomeric material, or a combination of materials.

Other materials for the substrate can include those formed of polymers,including oligomers, homopolymers, and copolymers resulting from eitheraddition or condensation polymerizations. Examples of suitable additionpolymers include, but are not limited to, acrylics such as thosepolymerized from methyl acrylate, methyl methacrylate, hydroxyethylmethacrylate, hydroxyethyl acrylate, acrylic acid, methacrylic acid,glyceryl acrylate, glyceryl methacrylate, methacrylamide, andacrylamide; vinyls such as ethylene, propylene, vinyl chloride, vinylacetate, vinyl pyrrolidone, vinylidene difluoride, and styrene. Examplesof condensation polymers include, but are not limited to, nylons such aspolycaprolactam, polylauryl lactam, polyhexamethylene adipamide, andpolyhexamethylene dodecanediamide, and also polyurethanes,polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate),polydimethylsiloxanes, and polyetherketone.

Beyond polymers, and depending on the type of device, the substrate canalso be formed of other materials such as metals (including metal foilsand metal alloys) and ceramics.

Aqueous Carrier

In one embodiment, the delivery composition includes a hydrophobicactive agent and a cationic delivery agent in a pharmaceuticallyacceptable aqueous carrier. As used herein, a “pharmaceuticallyacceptable carrier” refers to a carrier or diluent that does not causesignificant irritation to an organism and does not abrogate thebiological activity and properties of the administered composition. Inone embodiment, the aqueous carrier includes water or buffered saline.In a more particular embodiment, the aqueous carrier includesdeuterium-depleted water (DDW). In one embodiment, the hydrophobicactive agent and/or the cationic delivery agent are suspended in water.In one embodiment, the carrier includes a minor amount (e.g., less thanabout 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%) of abiocompatible solvent. As used herein, the term “biocompatible solvent”refers to a solvent that is considered non-toxic and does not elicit animmunological response at the amounts included in the carrier. Examplesof biocompatible solvents include, but are not limited to, ethanol,ethyl lactate, acetone, dimethylsulfoxide (DMSO), and combinationsthereof. In one embodiment, the hydrophobic active agent is suspended inwater as a coated therapeutic agent. In one embodiment, a mixing oragitation step can be performed in order to allow the hydrophobic activeagent to interface with the cationic delivery agent. In someembodiments, the cationic delivery agent surrounds and/or encapsulatesthe particulate hydrophobic active agent to form a coated active agentparticle.

In one embodiment, the pH of the composition is adjusted to at leastabout 5, 6 or 7 and up to about 7, 8 or 9.

Devices

It will be appreciated that embodiments herein include, and can be usedin conjunction with, various types of devices including, but not limitedto, drug delivery devices such as drug eluting balloon catheters,drug-containing balloon catheters, stents, grafts, and the like.

Some embodiments described herein can be used in conjunction withballoon expandable flow diverters, and self-expanding flow diverters.Other embodiments can include uses in contact with angioplasty balloons(for example, but not limited to, percutaneous transluminal coronaryangioplasty and percutaneous transluminal angioplasty). Yet otherembodiments can include uses in conjunction with sinoplasty balloons forENT treatments, urethral balloons and urethral stents for urologicaltreatments.

Other embodiments of the present disclosure can further be used inconjunction with micro-infusion catheter devices. In some embodiments,micro-infusion catheter devices can be used to target active agents tothe renal sympathetic nerves to treat, for example, hypertension.

Embodiments included herein can also be used in conjunction with theapplication of various active agents to the skin (for example, but notlimited to transdermal drug delivery).

Other exemplary medical applications wherein embodiments of the presentdisclosure can be used further encompass treatments for bladder neckstenosis (e.g. subsequent to transurethral resection of the prostrate),laryngotrachial stenosis (e.g. in conjunction with serial endoscopicdilatation to treat subglottic stenosis, treatment of oral cancers andcold sores and bile duct stenosis (e.g. subsequent to pancreatic,hepatocellular of bile duct cancer). By way of further example,embodiments herein can be used in conjunction with drug applicators.Drug applicators can include those for use with various procedures,including surgical procedures, wherein active agents need to be appliedto specific tissue locations. Examples can include, but are not limitedto, drug applicators that can be used in orthopedic surgery in order toapply active agents to specific surfaces of bone, cartilage, ligaments,or other tissue through physical contact of the drug applicator withthose tissues. Drug applicators can include, without limitation,hand-held drug applicators, drug patches, drug stamps, drug applicationdisks, and the like.

In some embodiments, drug applicators can include a surface having ahydrophilic polymer layer disposed thereon and coated therapeutic agentparticles disposed on the hydrophilic polymer layer, the coatedtherapeutic agent particles comprising a particulate hydrophobictherapeutic agent; and a vinyl amine polymer disposed over theparticulate hydrophobic therapeutic agent.

In use, various embodiments included herein can enable rapid transfer oftherapeutic agents to specific targeted tissues. For example, in someembodiments, a care provider can create physical contact between aportion of a drug delivery device including a therapeutic agent and thetissue being targeted and the therapeutic agent will be rapidlytransferred from the drug delivery device to that tissue. As such,precise control over which tissues the therapeutic agent is provided tocan be achieved.

One beneficial aspect of various of the embodiments herein is that thetherapeutic agent can be transferred from the drug delivery device orcoating to the targeted tissue very rapidly. In some embodimentssubstantial transfer of the therapeutic agent from the drug deliverydevice or coating to the tissue occurs in 30 minutes or less. In someembodiments substantial transfer of the therapeutic agent from the drugdelivery device or coating to the tissue occurs in 15 minutes or less.In some embodiments substantial transfer of the therapeutic agent fromthe drug delivery device or coating to the tissue occurs in 10 minutesor less. In some embodiments substantial transfer of the therapeuticagent from the drug delivery device or coating to the tissue occurs in 5minutes or less. In some embodiments substantial transfer of thetherapeutic agent from the drug delivery device or coating to the tissueoccurs in 2 minutes or less. In some embodiments substantial transfer ofthe therapeutic agent from the drug delivery device or coating to thetissue occurs in 1 minute or less.

In some embodiments, medical devices that can pass through a lumen of abodily structure are included herein. By way of example, medical devicesin accordance with embodiments herein can include capsular devices fortransitory placement within a lumen of the body.

Referring now to FIG. 16, the medical device 1602 includes a capsulehousing 1604 and an at least one moveable element 1606. In thisparticular embodiment, two moveable elements 1606 are shown. However, itwill be appreciated that the device can include any particular number ofmoveable elements. In some embodiments, the device can include from 1 to20 moveable elements. In some embodiments, the moveable elements can bearranged radially around the outside of the capsule housing 1604. Themedical device 1602 can have a total width 1608. In this view, themoveable elements are in a non-deployed position.

FIG. 16 also shows portions of a tissue 1610 and tissue walls 1612 thatform a lumen into which the medical device 1602 is disposed. It will beappreciated that the tissue 1610 can be from various parts of the body.By way of example, the tissue walls 1612 can be walls lining: a portionof the vasculature within a body, a portion of any segment of thealimentary canal (including but not limited to the esophagus, thestomach, the small intestine, or the large intestine), a portion of thebile duct system, of the like. In some embodiments, the tissue 1610 caninclude smooth muscle tissue.

Referring now to FIG. 17, the medical device 1602 includes a capsulehousing 1604 and an at least one moveable element 1606. In this view,the moveable elements are in a deployed position. The medical device1602 has a total width 1608 that is larger than the width when themoveable elements were in a non-deployed position. FIG. 17 also showsthe tissue 1610 and tissue wall 1612. With the moveable elements in adeployed position, a portion of moveable elements is in contact with thetissue walls 1612. As further described below, a coating, which caninclude various components (such as polymers, additives, excipients,and/or active agents) as described herein, can be disposed on themoveable elements. Thus, when the moveable elements are in contact withthe tissue walls, then the coating which includes an active agent canalso be in contact with the tissue walls so that the active agent can bedelivered to the tissue walls.

It will be appreciated that the device 1602 can include variouscomponents. By way of example, the device 1602 can include componentssuch as that described in U.S. Pat. Nos. 5,279,607, 7,797,033; and inU.S. Publ. App. No. 2010/0130837, the content of all of which is hereinincorporated by reference. Referring now to FIG. 18, the medical device1602 includes a capsule housing 1604, control circuitry 1814, disposedwithin the capsule housing 1604, and at least one moveable element 1606.The control circuitry 1814 can be configured to execute variousfunctions to control the device. In some embodiments, the controlcircuitry 1814 can be configured to cause the moveable element to movebetween a deployed position and a non-deployed position. The medicaldevice 1602 can also include telemetry circuitry 1816, which can beconfigured to receive and/or send information to an external device. Themedical device 1602 can also include power circuitry 1818 including, butnot limited to, components such as a battery, capacitor, or the like.The medical device 1602 can include moveable element actuator 1820. Insome embodiments, the moveable element actuator 1820 can include acomponent to provide a motive force to cause the moveable elements 1606to move between the deployed position and the non-deployed position. Theactuator 1820 can include various components such as a solenoid, linearactuator, piezoelectric actuator, electric motors of various typesincluding servo motors, and the like.

Referring now to FIG. 19, an embodiment of a moveable element 1606 isshown. The at least one moveable element 1606 can be a wing-shapedelement 1922. The at least one moveable element 1606 can include a frontportion 1924 and a back portion 1926. The front portion 1924 can serveas a pivot point with respect to the device 1602 in some embodiments.

Referring now to FIG. 20, the at least one moveable element 1606includes a substrate 2028 and a coating 2030 disposed over the substrate2028. The at least one moveable element 1606 can include outer surface2032. In various embodiment, the coating 2030 is disposed on the outersurface 2032. The coating 2030 can include various components asdescribed herein. In some embodiments, the coating can include ahydrophilic polymer layer and coated therapeutic agent particles. Insome embodiments, the coated therapeutic agent particles can include aparticulate hydrophobic therapeutic agent and a vinyl amine polymercomponent. The at least one moveable element 1606 can also include innersurface 2034. In some embodiments, the moveable element 1606 can have acurvature, such as shown in FIG. 20, which allows the moveable element1606 to fit more tightly against the device 1602 when the moveableelement 1606 is in a non-deployed position.

Referring now to FIG. 21, another embodiment of a moveable element 1606is shown. The at least one moveable element 1606 can include a shaft2136. The at least one moveable element 1606 can also include a paddle2138. The at least one moveable element 1606 can include a front side1924 and a back side 1926.

Method of Making

In one embodiment, the invention is directed towards methods of makingthe delivery compositions described herein. In one embodiment, thedelivery composition includes a hydrophobic active agent and a cationicdelivery agent in an aqueous carrier. In a more particular embodiment,the cationic delivery agent includes PEI. In another embodiment, thecationic delivery agent includes branched PEI. In a specific embodiment,the hydrophobic active agent is paclitaxel, sirolimus (rapamycin),everolimus, biolimus A9, zotarolimus, tacrolimus, and pimecrolimus andmixtures thereof.

In some embodiments, the hydrophobic active agent can be processed, forexample, by milling of the active agent. In some embodiments, processingof the hydrophobic active agent can include crystallization. In otherembodiments, processing of the hydrophobic active agent can includelyophilizing of the active agent.

In one embodiment, the hydrophobic active agent is suspended in anaqueous carrier such as water. By combining the hydrophobic active agentand a cationic delivery agent, coated active agent particles can beformed. By way of example, a cationic agent, in water or other aqueoussolvent, can be added to a hydrophobic active agent suspension. In someembodiments, a mixing or agitation step can be performed in order toallow the hydrophobic active agent to interface with the cationic agent.In some embodiments, the cationic agent will surround or encapsulate theparticulate hydrophobic active agent. In one embodiment, the hydrophobicactive agent has a particle size of at least about 0.1 μm, 0.2 μm, 0.3μm, 0.4 μm, 0.5 μm or 1 μm and less than about 10 μm, 5 μm, 4 μm, 3 μm,2μm or 1 μm.

In one embodiment, an active agent solution or suspension is first madeby combining a hydrophobic active agent with an aqueous solvent to forman active agent solution or suspension. After the active agent solutionor suspension is formed, the cationic delivery agent is added to form adelivery composition. In one embodiment, the hydrophobic active agent iscrystallized before it is combined with the aqueous solvent to form theactive agent solution or suspension. In another embodiment, thehydrophobic active agent is amorphous when it is combined with theaqueous solvent to form the active agent solution or suspension. Inanother embodiment, the cationic delivery agent is combined with anaqueous solvent to form a cationic delivery agent solution before thecationic delivery agent is combined with the active agent solution orsuspension. In one embodiment, the pH of the cationic delivery agentsolution is buffered to between about 5 and 9 before the cationicdelivery agent is added to the active agent solution or suspension.

In another embodiment, the delivery composition is made by combining thehydrophobic active agent and the cationic delivery agent to form anactive agent mixture. In one embodiment, the active agent mixturecomprises solid hydrophobic active agent and pure or neat cationicdelivery agent. In one embodiment, the solid hydrophobic active agent iscrystalline. In another embodiment, the solid hydrophobic active agentis amorphous. In one embodiment, the method includes a step ofcrystallizing the hydrophobic active agent before it is combined withthe cationic delivery agent. In another embodiment, the hydrophobicactive agent is amorphous when it is combined with the cationic deliveryagent. In one embodiment, the method includes a step of crystallizingthe mixture of solid hydrophobic active agent and pure or neat deliveryagent before combining the mixture with an aqueous carrier to form thedelivery composition. In another embodiment, a mixture containingcrystalline hydrophobic active agent and pure or neat delivery agent iscombined with the aqueous carrier to form the delivery composition. Ingeneral, when solid hydrophobic active agent and solid hydrophobiccationic delivery agent are combined to form a mixture, the ratio ofsolid hydrophobic active agent:cationic delivery agent is less thanabout 1:5 to prevent the cationic delivery agent from solubilizing thehydrophobic active agent.

In various embodiments, coating solutions herein, both as compositionsand as used with methods herein, can have a pH that is in a range ofabout 2.0 to about 8.0. In various embodiments, the pH of one or morecoating solutions herein can be in a range having a lower bound and anupper bound, wherein the lower bound of the range can be any of 2.0,2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, or 7.5 and the upperbound of the range can be any of 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0,6.5, 7.0, 7.5, 8.0, wherein the upper bound of the range is higher thanthe lower bound of the range.

Kits and Articles of Manufacture

Another embodiment of the invention is directed towards kits andarticles of manufacture. In particular, the present invention provideskits or packages including the delivery compositions described herein.In one embodiment, the invention provides a kit that includes one ormore of the components of the delivery composition. As used herein“components of the delivery composition” can refer to one or morehydrophobic active agents, one or more cationic delivery agents, one ormore pharmaceutically acceptable aqueous carriers, and any otheradditive, diluent, excipient, adjuvant, emulsifier, buffer, stabilizer,preservative included in the delivery composition. In one embodiment,the kit includes one or more hydrophobic active agents and one or morecationic delivery agent and instructions for combining the hydrophobicactive agent and cationic delivery agent to form a delivery compositionsuitable for local administration. In one embodiment, the cationicdelivery agent includes PEI. In another embodiment, the cationicdelivery agent includes branched PEI. In a specific embodiment, thehydrophobic active agent is paclitaxel, sirolimus (rapamycin),everolimus, biolimus A9, zotarolimus, tacrolimus, and pimecrolimus andmixtures thereof.

In one embodiment, the kit includes at least about 1 mg/ml and up toabout 25 mg/ml cationic delivery agent and at least about 5 mg/ml and upto about 125 mg/ml hydrophobic active agent, wherein the components arepackaged individually, or combined, for example as a mixture of solidsor as a liquid solution or suspension. In one embodiment, the kitincludes at least about 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, or10 mg/ml, 15 mg/ml, 20 mg/ml, or 25 mg/ml or up to about 25 mg/ml, 50mg/ml, 75 mg/ml, 100 mg/ml, 125 mg/ml or 150 mg/ml hydrophobic activeagent. In one embodiment, the kit includes at least about 0.1 mg/ml, 0.5mg/ml, 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, or 5 mg/ml and up to about 5mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml or 25 mg/ml cationic delivery agent.In one embodiment, the kit includes cationic delivery agent:hydrophobicactive agent at a ratio of at least 1:25, for example, between about 1:1and about 1:25, or at least about 1:2, 1:5 or 1:10 and up to about 1:10,1:15, 1:20 or 1:25.

A number of packages or kits are known in the art for the use indispensing pharmaceutical agents. The components of the deliverycomposition (for example, the hydrophobic active agent, the cationicdelivery agent, the pharmaceutically acceptable aqueous carrier and/orany other additives) may be individually formulated or co-formulated andfilled into suitable containers such as syringes, ampoules, or vials. Itis envisioned that the aqueous carrier also may be provided in anothercontainer in the kit. The kits of the present invention also willtypically include a means for containing the vials in close confinementfor commercial sale such as, for example, injection or blow-moldedplastic containers into which the desired vials are retained. In oneembodiment, the kit includes an instrument for administration of thedelivery composition, such as an inhalant, syringe, pipette, eyedropper, measuring spoon, or other such instrument, which can be used toapply the delivery composition to the desired tissue or organ of thepatient.

In one embodiment, the kit provides one or more of the components of thedelivery composition and instructions for combining the components foradministration. In one embodiment, one or more of the components of thedelivery composition in the kit is provided in dried or lyophilizedforms. In one embodiment, the hydrophobic active agent, the cationicdelivery agent, or both are provided as dried solids, individually or asa mixture. In another embodiment, the hydrophobic active agent, thecationic delivery agent, or both are provided as lyophilized solids,individually or as a mixture. In one embodiment, the hydrophobic activeagent, the cationic delivery agent, or both are provided as amorphoussolids, individually or as a mixture. In another embodiment, thehydrophobic active agent, the cationic delivery agent, or both areprovided as crystalline solids, individually or as a mixture. When oneor more components are provided as a dried solid, reconstitutiongenerally is by the addition of a suitable aqueous carrier. In oneembodiment, the aqueous carrier is water.

In another embodiment, one or more of the components of the deliverycomposition is provided as a solution or suspension. In one embodiment,the hydrophobic active agent, the cationic delivery agent, or both areprovided as a solution or suspension, individually or as a mixture. Forexample, if individually provided, two solution components can beseparated in a dual delivery syringe for ease of delivery to the site(for example dual delivery syringes and mini-dual delivery syringesavailable from Plas-Pak, Inc, Norwich, Conn.). In some instances,contents of a dual delivery syringe can be lyophilized to provide for adual delivery syringe that contains a solution or suspension in one sideand a dry powder in the other. Alternatively, the dual delivery syringecan contain lyophilized dry powder in both sides of the dual syringe. Itis well known in the art that the lyophilized powder can bereconstituted at the point of use with physiologically acceptable fluid,such as phosphate buffered saline (PBS).

In one embodiment, one or more of the components of the deliverycomposition are provided as a dried solid in a container, individuallyor as a mixture, for example, as a crystallized solid or an amorphoussolid, and are reconstituted with a pharmaceutically acceptable carrierprior to administration. In other embodiments, one or more of thecomponents of the delivery composition are provided in as a liquid, in acontainer, individually or as a mixture, that may be administered withor without dilution. In one embodiment, one of the components of thedelivery composition may be provided in solid form, which, prior toadministration to a patient, is reconstituted with an aqueous liquid andanother component of the delivery composition may be provided as aliquid solution or suspension, wherein the components are combined priorto administration. Each container may contain a unit dose of the activeagent(s).

Methods of Use

The invention also provides a method for delivering a therapeuticallyeffective amount of a hydrophobic active agent to a tissue, organ ororgan system of a patient. In a more particular embodiment, theinvention provides a method for local delivery of a therapeuticallyeffective amount of a hydrophobic active agent to a solid tissue ororgan of a patient. While not wishing to be bound by theory, it isbelieved that combining the hydrophobic active agent with a cationicdelivery agent such as PEI improves adhesion of active agent to thetissue or organ surface, thereby increasing bioavailability and uptakeof the hydrophobic active agent by tissue or organ to which it isapplied. The cationic delivery agent may also disrupt some of thejunctions between cells to increase permeability and allow the activeagent to penetrate into the tissue or organ. It appears that the abilityof the cationic delivery agent to improve therapeutic performance ismost pronounced when used in combination with hydrophobic active agents.It is believed that more soluble hydrophilic active agents are moreeasily washed away from the surface of the tissue or organ byphysiological fluids.

As used herein, the term “tissue” refers to an ensemble of similar cellsfrom the same origin, that together carry out a specific function.Animal tissues can be grouped into four basic types: connective, muscle,nervous, and epithelial. Connective tissues are fibrous tissues made upof cells scattered throughout an extracellular matrix. Connective tissuehelps maintain the shape of organs and helps holds them in place. Boneis an example of connective tissue. Muscle tissue functions to produceforce and cause motion, either locomotion or movement within internalorgans. Muscle tissue can be separated into three categories: visceralor smooth muscle, which is found in the inner linings of organs;skeletal muscle, in which is found attached to bone providing for grossmovement; and cardiac muscle which is found in the heart. Nervous tissuefunctions to transmit messages in form of impulses. In the centralnervous system, nervous tissue forms the brain and spinal cord. In theperipheral nervous system, nervous tissue forms the cranial nerves andspinal nerves. Epithelial tissue helps to protect organisms frommicroorganisms, injury, and fluid loss. The cells comprising anepithelial layer are linked via semi-permeable, tight junctions; hence,this tissue provides a barrier between the external environment and theorgan it covers. In addition to this protective function, epithelialtissue may also be specialized to function in secretion and absorption.Epithelial tissues include cells that cover organ surfaces such as thesurface of the skin, the airways, the reproductive tract, and the innerlining of the digestive tract.

As used herein, the term “organ” refers to a functional grouping of oneor more tissues. Functionally related organs may cooperate to form organsystems. Examples of organs and organ systems found in mammals include,but are not limited to: the cardiovascular system, which includes organssuch as the heart and blood vessels; the digestive system, whichincludes organs such as salivary glands, esophagus, stomach, liver,gallbladder, pancreas, intestines, colon, rectum and anus; the endocrinesystem, which includes endocrine glands such as the hypothalamus,pituitary gland, pineal body or pineal gland, thyroid, parathyroid andadrenal glands; the excretory system, which includes organs such askidneys, ureters, bladder and urethra; the immune system, which includestonsils, adenoids, thymus and spleen; the integumentary system, whichincludes skin, hair and nails; the muscular system, which includesvoluntary and involuntary muscles; the nervous system, which includesbrain, spinal cord and nerves; the reproductive system, which includesthe sex organs, such as ovaries, fallopian tubes, uterus, vagina,mammary glands, testes, vas deferens, seminal vesicles, prostate andpenis; the respiratory system, which includes the pharynx, larynx,trachea, bronchi, lungs and diaphragm; and the skeletal system, whichincludes bones, cartilage, ligaments and tendons. As used herein, theterms “tissue” and “organs” refer to solid tissues or organs, ratherthan blood or other biological liquids such as spinal fluid, amnioticfluid or peritoneal fluid.

As used herein, an “individual” or a “patient” is a vertebrate, forexample, a mammal. The term “mammal” can also refer to any animalclassified as a mammal, including humans, domestic and farm animals, andzoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. In amore particular embodiment, the mammal is human.

The term “effective amount” refers to an amount effective, at dosagesand for periods of time necessary, to achieve the desired therapeutic orprophylactic result. A “therapeutically effective amount” of thedelivery composition of the invention may vary according to factors suchas the disease state, age, sex, and weight of the individual, and theability of the substance/molecule, agonist or antagonist to elicit adesired response in the individual. A therapeutically effective amountis also one in which any toxic or detrimental effects of the compositionare outweighed by the therapeutically beneficial effects. A“prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically but not necessarily, since a prophylacticdose is used in subjects prior to or at an earlier stage of disease, theprophylactically effective amount may be less than the therapeuticallyeffective amount.

In one embodiment, the invention provides a method for treating a tissueor organ of a patient. As used herein, the terms “treat”, “treating” and“treatment” refer to clinical intervention in an attempt to alter thenatural course of the individual or cell being treated, and can beperformed either for prophylaxis or during the course of clinicalpathology. Desirable effects of treatment include preventing occurrenceor recurrence of disease, alleviation of symptoms, diminishing of anydirect or indirect pathological consequences of the disease, decreasingthe rate of disease progression, amelioration or palliation of thedisease state, and remission or improved prognosis. As used herein, theterms “prevent”, “preventing” and “prevention” refer to a method forpreventing an organism from acquiring a disorder.

The delivery composition may be a topical, syringable, or injectableformulation; and is suitable for local delivery of the active agent. Fortopical administration, the delivery composition is applied directlywhere its action is desired. Methods for topical delivery include theuse of ointments, creams, emulsions, solutions, suspensions and thelike. In other embodiments, the delivery composition is administered byapplication through a cannula, by injection, or as part of a lavage.Compositions for these types of local delivery can include solutions,suspensions and emulsions.

Examples of local administration include, but are not limited to,epicutaneous administration (i.e., application onto the skin);inhalation, for example, with asthma medications; as an enema for localadministration to the bowel; ocular, for example, as eye drops for localadministration to the conjunctiva; aural, for example, as ear drops; orintranasal. In other embodiments, an active agent can be administeredlocally from a device such as a balloon catheter. In another embodiment,local administration includes the lavage of an open wound, the lavagecontaining delivery compositions described herein with antimicrobials orother wound healing medicaments. In a more particular embodiment, localadministration includes oral lavage, for example, a mouthwash.

In some embodiments, the delivery composition can be administered usinga balloon catheter. The delivery composition can be infused through alumen or lumens of a balloon catheter to administer the composition tothe desired site where the drug effect is warranted. For example, thesite can be a segment of an artery, vein or neurovascular. The methodallows for isolation and subsequent perfusion of the target organ (e.g.for tumor treatment). One specific embodiment of administration can bethe use of a dual occlusion balloon (e.g. TAPAS balloon system availablefrom Spectranectics International, BV, Leusden, The Netherlands) forprecise targeting of a treatment area (e.g. intra-arterially). Use ofdelivery compositions as disclosed herein can increase targeting of thetreatment area with the drug being delivered, thus further minimizingunwanted systemic effects of the drug. Other balloon catheter methods ofuse include balloon sinuplasty (e.g. Relieva® and Relieva Ultirra™;available from Acclarent, Menlo Park, Calif.)

In yet other embodiments, a medical device such as a balloon cathetercan be coated with the delivery composition described herein. In oneembodiment, the balloon catheter can be coated in a collapsed state. Inanother embodiment, the balloon catheter can be coated in a partially orfully expanded state. In one embodiment, the balloon catheter can becoated with the coating materials described herein and a bioactivematerial such as a chemical ablative (e.g. vincristine, paclitaxel) andfurther used for renal artery denervation therapy for hypertension.

Delivery compositions of the present disclosure can also be used inconjunction with microinfusion catheters. Such catheters can be used todeliver drug, for example, for renal denervation for direct infusioninto the vessel wall (Bullfrog® and Cricket™ microinfusion cathetersavailable from Mercator MedSystems, Inc.). Microinfusion catheters withdelivery compositions of the present disclosure can also be used to forman embolic block, such as in neurovascular applications or treatment ofthe vascular supply of tumors. Other neurovascular methods of useinclude, but are not limited to, brachytherapy treatment for braincancer applications (GliaSite Radiation Therapy System available fromIsoRay, Medical, Richland, Wash.).

Delivery compositions described herein can also be used in connectionwith treating stenosis such as bladder neck stenosis (BNS), acomplication associated with transurethral resection of the prostate;laryngotracheal stenosis, for example, in conjunction with serialendoscopic dilation to treat subglottic stenosis; and bile ductstenosis, for example, subsequent to pancreatic, hepatocellular or bileduct cancer.

Delivery compositions described herein can be combined with treatmentsthat use RF-susceptible microparticles to improve uptake of themicroparticles in the tissue at the site of the tumor or other targetedorgan. Other embodiments for topical administration include, but are notlimited to, oral cavity delivery of chemotherapeutics, for example withmouthwashes. Additionally, studies have shown that delivery of rapamycinto the oral cavity can prevent radiation-induced mucositis and that itcan be desirable to reduce the systemic levels of rapamycin to avoidtoxicities associated with the drug (Cell Stem Cell, Sep. 7, 2012, Vol.11:3, pp. 287-288).

Delivery compositions described herein can be used to increasedrug-uptake in the lung. One embodiment envisioned to be used fordelivery compositions for inhalation therapy can be a metered-doseinhaler (available from 3M Company, St. Paul, Minn.). Compositionsdescribed herein can increase drug uptake in the lung to provide forimproved speed of drug effect, an important aspect when treating diseasestates such as asthma.

Other methods of use include treatment of joint disorders (e.g.arthritis). Local injections of drug (e.g. cortisone) are desirable tobe kept at the site of the affected joint for extended term.

Some embodiments of the method of use include localized treatment of thelining of the esophagus. Barrett's esophagus (pre-cancer esophaguslining) after BARRX treatment (ablation) requires delivery of localhealing agents to the affected site for improved outcomes. Deliverycompositions disclosed herein can increase uptake of healing agents bythe treated esophagus.

Other exemplary methods of use for the local delivery compositionsdescribed herein include direct injections into a cancerous tumor,intraperitoneal tumor treatment, and sclerotherapy. Additionally,percutaneous delivery systems of biologics for the treatment ofcardiovascular disease can use the delivery composition of the presentdisclosure. Treatments such as those under the trade name JVS-100,promotes tissue repair through recruitment of endogenous stem cells tothe damaged organ (available from BioCardia, Inc, San Carlos, Calif.).These devices allow delivery into the heart using the Helical InfusionCatheter for transendocardial intramyocardial injection of therapies(also from BioCardia).

Additional Embodiments

As described above, some embodiments can include a hydrophilic base coator layer. In some embodiments, a hydrophilic polymer solution is formedby combining a hydrophilic polymer with one or more solvents. Exemplaryhydrophilic polymers are described in greater detail above. Thehydrophilic polymer solution can then be applied to a suitablesubstrate, such as an expandable balloon disposed on a catheter shaft.Many different techniques can be used to apply the hydrophilic polymersolution to the substrate. By way of example, exemplary techniques caninclude brush coating, drop coating, blade coating, dip coating, spraycoating, micro-dispersion, and the like.

In some embodiments, such as where a photo-polymer is used to form thehydrophilic layer, an actinic radiation application step can beperformed in order to activate latent photoreactive groups on thehydrophilic polymer or on a cross-linker in order to covalently bond thehydrophilic polymer the substrate surface. By way of example, afterapplying the hydrophilic polymer solution to the substrate, the devicecan be subjected to UV exposure at a desirable wavelength for a periodof time.

Next a hydrophobic active agent can be obtained and processed in orderto prepare it for deposition. In some embodiments, processing of thehydrophobic active agent can include steps such as milling of the activeagent. In some embodiments, processing of the hydrophobic active agentcan include steps such as recrystallization of the active agent. In someembodiments, processing of the hydrophobic active agent can includelyophilizing of the active agent.

In various embodiments, the hydrophobic active agent, as a particulate,can be suspended in water. Using the hydrophobic active agent and avinyl amine polymer, coated therapeutic agent particles can be formed.By way of example, a vinyl amine polymer, in water or a differentsolvent, can be added to the hydrophobic active agent suspension. Invarious embodiments, a mixing or agitation step can be performed inorder to allow the hydrophobic active agent to interface with the vinylamine polymer. In some embodiments, the vinyl amine polymer willsurround the particulate hydrophobic active agent.

In some embodiments, a nucleic acid solution can be added to themixture, either before or after addition of the vinyl amine polymer andthe mixing/agitation steps. In some embodiments, an additive componentsuch as those described above can be added to the mixture. The mixturecan be applied to the substrate of a device, either directly or on topof a hydrophilic base coat. By way of example, exemplary techniques forapplication can include brush coating, drop coating, blade coating, dipcoating, spray coating, micro-dispersion and the like.

The solution including the vinyl amine polymer and the hydrophobicactive agent can include various amounts of the active agent. By way ofexample, the solution can include from 1 to 500 mg/ml of the activeagent in some embodiments. In some embodiments the solution can includefrom 10 to 250 mg/ml of the active agent. In some embodiments, thesolution can include form 50 to 200 mg/ml. In some embodiments, thesolution can include form 100 to 200 mg/ml. In some embodiments, thesolution can include form 100 to 180 mg/ml. In some embodiments, thesolution can include about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110,120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250mg/ml of the active agent wherein each of those amounts can serve as theupper or lower bound of a range.

After application, the composition can be allowed to dry. In the contextof drug eluting balloon catheters or a drug-containing balloon catheter,for example, the balloons can be folded, pleated and sheathed in asheath. In some embodiments, balloons can be placed in an oven for aperiod of time.

In some embodiments of the present disclosure, an active agent that isnot hydrophobic can be modified to be essentially hydrophobic fordisposition on the hydrophilic polymer layer. Exemplary modificationscan include the preparation of prodrugs, whereby the hydrophobicity ofthe active agent can be modified by covalent linkage to a polymer. Otherexemplary prodrugs can include an active agent that is formed in-situ bybond cleavage of the prodrug. Other exemplary modifications can include,but are not limited to, particles (e.g. nanoparticles or microparticles)containing the active agent encapsulated in a hydrophobic polymer. Insome embodiments the hydrophobic polymer can be biodegradable, releasingthe active agent upon delivery to the targeted tissue. Other exemplarymodifications can include, but are not limited to, micelles or otherconstructs of the like with altered hydrophobicity, formed as a resultof the interaction between the active agent and a lipid additive.

The present invention may be better understood with reference to thefollowing examples. These examples are intended to be representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

EXAMPLES

As used in the Examples, the term “jar-Milled Paclitaxel” refers toPaclitaxel (LC laboratories) that was suspended in water at 65 mg/mL andmilled using 5 mm stabilized zirconia 5×5 mm cylindrical beads (StanfordMaterials Corp). After milling for 18 hours the slurry was removed fromthe beads and lyophilized. The term “sonicated Paclitaxel” refers toPaclitaxel crystals that were obtained by suspending paclitaxel (LCLaboratories) in water at 50 mg/mL. The paclitaxel was micronized usinga sonic probe for 30 seconds, and leaving the resulting suspension forthree days at room temperature on an orbital shaker with a 1 hoursonication treatment per day in a sonic bath over the course of thethree days. The mixture was lyophilized.

Example 1 Polyethylenimine (PEI) Mediated Transfer of Paclitaxel (PTX)to Surfaces

Delivery of paclitaxel to surfaces with or without seeded endothelialcells was studied in-vitro using untreated 24-well polystyrene tissueculture plates (TCPS); Matrigel™ coated 24-well cell culture plates (BDMatrigel™ Matrix Thin-Layer cell; available from Becton DickinsonBiosciences, Franklin Lakes, N.J.), or 24-well cell culture platestreated with heparin-containing HP01 coating or collagen containing CL01coating (available from SurModics, Eden Prarie, Minn.). Human coronaryendothelial cells (HCAECs, available Lonza, Walkersville, Md.) werecultured in EGM™-2MV growth media (available from Lonza, Walkersville,Md.). One day prior to paclitaxel transfer studies, cells were seed inthe various culture plates at 50,000 cells per well in 0.5 mL of medium.Suspensions of paclitaxel (available from LC Laboratories, Woburn,Mass.) in water were prepared at 55.2 mg/ml paclitaxel with or withoutPEI (available from Polysciences, Warrington, Pa., MW=750 kDa) at 4.8mg/ml. The suspensions were sonicated briefly. Resulting suspensions(6.7 μL) were added to cell media (100 μL) and put in the cell cultureplates and incubated for 3 minutes. Suspensions were also added to thedifferent 24-well plates with 100 μL medium (100 μL) but without seededcells. After incubation plates were rinsed three times with phosphatebuffered saline (500 μL per well) and then allowed to dry overnight.Paclitaxel remaining in plates as a result of adhesion was dissolved in250 μL methanol and quantified by HPLC. The amount of transferredpaclitaxel is shown in FIG. 1.

Example 2 Delivery of Paclitaxel to Surfaces with or without SeededEndothelial Cells

Delivery of paclitaxel to surfaces with or without seeded endothelialcells was studied in-vitro using Matrigel™ coated 96-well cell cultureplates (BD Matrigel™ Matrix Thin-Layer cell, available from BectonDickinson Biosciences, Franklin Lakes, N.J.). Human coronary endothelialcells (HCAECs, available from Lonza, Walkersville, Md.) were cultured inEGM™-2MV growth media (available from Lonza, Walkersville, Md.). One dayprior to paclitaxel transfer studies, cells were seed in the variousculture plates at 20,000 cells per well in 0.2 mL of medium. Suspensionsof paclitaxel (LC Laboratories, Woburn, Mass.) in water were prepared at11 mg/ml paclitaxel with or without PEI (available from Polysciences,Warrington, Pa.; MW=750 kDa) at 1 mg/ml. Suspensions were sonicatedbriefly prior to use. Resulting suspensions (5 μL) were added to 0.1 mLof cell media and put in the cell culture plates and incubated for 3minutes. Suspensions were also added to the Matrigel™ coated plate with0.1 mL medium but without seeded cells. After incubation plates wererinsed three times with phosphate buffered saline (0.2 mL per well) andthen allowed to dry overnight. Paclitaxel remaining in plates as aresult of adhesion was dissolved in 250 μL methanol/0.1% acetic acid andquantified by HPLC. The amount of transferred paclitaxel is shown inFIG. 2.

Example 3 Polyethyleneimine (PEI) Mediated Transfer of Paclitaxel (PTX)to Endothelial Cell Surface or Extracellular Matrix Surfaces

Delivery of paclitaxel to endothelial cells and tissue was studied invitro using cells grown on Matrigel™ coated cell culture plates. Humancoronary endothelial cells (HCAECs, Lonza, Walkersville, Md.) werecultured in EGM™-2MV growth media (Lonza, Walkersville, Md.). One dayprior to paclitaxel transfer studies, cells were seed in 96 well BDMatrigel™ Matrix Thin-Layer cell culture plates at 20,000 cells per wellin 0.2 mL of medium. Suspensions of paclitaxel (LC Laboratories, Woburn,Mass.) in water were prepared at 11 mg/ml paclitaxel and with PEI(Polysciences, Warrington, Pa.; MW=750 kDa) or PAMAM, ethylene diaminecore, gen 4, dendrimer (Sigma, Milwaukee, Wis.; 14,214 Da) at 0.96 mg/mL(92:8 w/w ratio) or iopromide at 11 mg/mL (IOPR, 1:1 w/w ratio).Suspensions were sonicated briefly prior to use. Resulting suspensions(5 μL) were added to the cell culture plates and incubated for 3 or 10minutes. Suspensions were also added to Matrigel™ coated plates withmedium but without cells. After incubation plates were rinsed threetimes with phosphate buffered saline (200 μL per well) and then allowedto dry overnight. Paclitaxel remaining in plates was dissolved inmethanol (250 μL) and quantified by HPLC. The amount of transferredpaclitaxel is shown in FIG. 3.

Example 4 Adhesion of Paclitaxel to Surfaces in the Presence of Heparin

Adhesion of paclitaxel to surfaces in the presence of heparin at variedconcentrations with or without seeded endothelial cells was studiedin-vitro using Matrigel™ coated 96-well cell culture plates (BDMatrigel™ Matrix Thin-Layer cell, BD Biosciences, San Jose, Calif.).Human coronary endothelial cells (HCAECs, Lonza, Walkersville, Md.) werecultured in EGM™-2MV growth media (Lonza, Walkersville, Md.). One dayprior to paclitaxel transfer studies, cells were seed in the variousculture plates at 20,000 cells per well in 0.2 mL of medium. Prior toadding paclitaxel, heparin (Sodium Salt, Celsus, Cincinnati, Ohio) wasdissolved in growth medium at concentrations of 25, 5, 1, 0.2, 0.04,0.008 and 0.0016 mg/ml and media in cell culture plates was replacedwith heparin containing medium. Suspensions of paclitaxel (LCLaboratories, Woburn, Mass.) in water were prepared at 11 mg/mlpaclitaxel with or without PEI (Polysciences, Warrington, Pa.) at 1mg/ml. Suspensions were sonicated briefly prior to use. 5 μL ofsuspensions were added to the growth media in plates with and withoutcells and incubated for 4 minutes. After incubation plates were rinsedthree times with phosphate buffered saline (0.2 mL per well) and thenallowed to dry overnight. Paclitaxel remaining in plates as a result ofadhesion was dissolved in methanol (60 μL) and quantified by HPLC. Theamount of transferred paclitaxel with and without PEI and varyingheparin concentrations is shown in FIGS. 4 and 5.

Example 5 Adhesion of Paclitaxel to Surfaces with or without SeededEndothelial Cells

Adhesion of paclitaxel to surfaces with or without seeded endothelialcells was studied in-vitro using Matrigel™ coated 96-well cell cultureplates (BD Matrigel™ Matrix Thin-Layer cell). Human coronary endothelialcells (HCAECs, Lonza, Walkersville, Md.) were cultured in EGM™-2MVgrowth media (Lonza). One day prior to Paclitaxel transfer studies,cells were seeded in wells of column 7 to 12 of the culture plate at20,000 cells per well in 0.2 mL of medium. After 24 hours incubation themedium was replaced with 100 ul fresh medium in all wells. Suspensionsof Paclitaxel (LC Labs, ‘sonicated’) in aqueous branched PEI solutionswere prepared at 11 mg/ml paclitaxel and PEI at 1 mg/ml. Branched PEI ofdifferent molecular weights were used: 750 kDa from both polysciencesand Sigma, 70 kDa and 25 kDa from Sigma, 1200 Da and 600 Da frompolysciences. All suspensions were sonicated briefly prior to use toensure that all components were well distributed. In 12 wells performulation (6 with and 6 without HCAEC seeded on top of the matrigel):5 μL of the suspension was added to 0.1 mL of cell media. The plate wasincubated for 3 minutes during which time the suspension was allowed tosettle. After incubation the plate was rinsed three times with phosphatebuffered saline (0.2 mL per well) and then allowed to dry overnight.Paclitaxel remaining in the plate as a result of adhesion was dissolvedin 250 μL methanol/0.1% acetic acid and quantified by HPLC. The amountof transferred paclitaxel is shown in FIG. 6.

Example 6 Preparation of Materials

A. Preparation of (NVF-Co-NVP) Polymers A-D (Varying Molar Ratios of1-Vinyl-2-Pyrrolidinone (NVP) and N-Vinylformamide (NVF))

Deionized water (72.2 g), N-vinylformamide (NVF, 5.85 g; available fromSigma Aldrich, Milwaukee, Wis.), N-vinylpyrrolidone (NVP, 9.14 g;available from Sigma Aldrich), and2,2′-Azobis(2-methylpropionamidine)dihydrochloride (Vazo 56WSP; 0.192 g;available from Sigma-Aldrich) were placed in a 100 ml bottle with screwtop cap. The solution was sparged with nitrogen for 10 minutes. The jarwas capped and the solution was rotated in an oven at 55° C. overnight.A portion of the ensuing aqueous solution (˜6.7%) was placed in dialysistubing (MWCO 12-14 kDa; SPECTRA/POR® available from VWR, Radnor, Pa.)and dialyzed against water for 3 days. The dialyzed solution waslyophilized following 5 stages at the temperatures, pressures and timeslisted below in Table 2. A white solid (0.92 g) resulted.

TABLE 2 Stages 1 2 3 4 final Temperature (° C.) −10 0 10 25 25 Pressure(milltorr) 400 200 100 50 <20 Time (hours) 3 3 3 3 >5*

PVP (4.0 g; K-30; available from BASF, Port Arthur, Tex.) was dissolvedin DI water (19.2 mL). A proton NMR was recorded for the PVP solution.The solution was treated with NaOH (0.15 g. of 50% aq.) and rotated inan oven at 80° C. overnight. The polymer solution was neutralized usingHCl conc (0.2 mL; final pH=3-4). After neutralization the solution wasdifiltered using 10 kDa membrane (0.10 m² pellicon mini cassette;available from Millipore; Billerica, Mass.) against DI water. Thesolution was lypholized as described above to yield 3.12 g white solid.A proton NMR was recorded for the PVP treated with NaOH. In comparingthe proton NMR spectrum of PVP against the proton NMR spectrum of PVPtreated with NaOH, no differences could be seen between the spectra.

Four co-polymers of various monomer ratios were made as shown in Table3.

TABLE 3 Mole N- N- Vazo dialyzed and Weight of Polymer % VinylformamideVinylpyrrolidone 56WSP Water lyophilized polymer ID NVF (g) (g) (g) (g)(g) isolated (g) Polymer A 100.00 15.000 0.000 0.250 72.180 5.290 0.771Polymer B 50.00 5.852 9.144 0.192 53.380 4.570 0.920 Polymer C 5.000.490 14.511 0.165 42.350 3.830 1.120 Polymer D 0.00 0.000 15.000 0.16141.350 3.770 1.060

B. Preparation of Polymers A10, A20, A50 and A100 (Varying Hydrolysis ofpNVF)

Polymer solution A was treated with various amounts of NaOH and rotatedin an oven at 80° C. overnight. This reaction is illustrated in equationI below.

The polymer solutions were neutralized using HCl conc. (polymer A10 andPolymer A20 solutions adjusted to pH=9.0; polymer A50 and Polymer A100solutions adjusted to pH=10.0), dialyzed, and lyophilized (as describedabove). Table 4 lists the reagents used and amounts.

TABLE 4 Weight of Lyophilized polymer Polymer NVF NaOH mEquiv of polymerPolymer (% solution A Weight (calculated solution NaOH weight %Hydrolysis hydrolysis; theory) (g) (g calculated) meq) (50%, g)(calculated) (g) (by NMR analysis) Polymer A10 (10) 20.4 3.5 31.5 0.2523.15 1.07 3.3 Polymer A20 (20) 20.4 3.5 31.5 0.504 6.3 1.15 14.9 PolymerA50 (50) 20.4 3.5 31.5 1.26 15.75 1.18 43.3 Polymer A100 (100) 20.4 3.531.5 2.56 32 1.04 75.1

C. Preparation of Polymers E-J

A second series of co-polymers was made according to Table 5. In step 1the monomers were placed in a bottle, sparged with nitrogen gas for 10minutes, and rotated in an oven at the selected temperature for 14hours. In step 2, each polymer solution in its entirety was diluted withwater, treated with NaOH, and refluxed for at least 20 hours. Thereaction for copolymers including N-vinyl formamide and N-vinylpyrrolidone is illustrated in Equation II below.

TABLE 5 Step 1 Polymerization Step 2 Hydrolysis N- N- VazoPolymerization Added Added Mole % Vinylformamide Vinylpyrrolidone 56WSPWater temperature water 50% NaOH Polymer ID NVF (g) (g) (g) (ml) (° C.)(ml) solution (g) Polymer E 100.00 15.000 0.000 0.244 72.18 70 428.033.76 Polymer F 80.00 10.785 4.215 0.223 63.51 55 475.7 24.30 Polymer G60.00 7.346 7.653 0.199 56.46 55 483.5 16.50 Polymer H 40.00 4.48210.515 0.183 50.65 55 489.9 10.10 Polymer I 20.00 2.064 12.931 0.16845.60 55 495.3 4.70 Polymer J 10.00 1.000 14.000 0.162 43.40 70 457.02.24

Each hydrolyzed polymer solution was difiltered using a 10 kDa membrane(0.10 m² pellicon mini cassette; available from Millipore; Billerica,Mass.) until the pH of the permeate was less than 7, which requiredabout 15 to 20 liters of permeate.

Paclitaxel crystals were obtained by suspending paclitaxel (LCLaboratories; Woburnn, Mass.) in water at 50 mg/mL. The paclitaxel wasmicronized using a sonic probe for 30 seconds, and leaving the resultingsuspension for three days at room temperature on an orbital shaker witha 1 hour sonication treatment per day in a sonic bath over the course ofthe three days (“Sonicated Paclitaxel”). The mixture was lyophilized.

Unless otherwise indicated nylon balloons (20×3.5 mm) were used in allstudies.

Hydrophilic basecoats (R) were deposited onto the nylon balloonsurfaces. The hydrophilic basecoat solution included 6.25 g/L polyvinylpyrrolidone (PVP) with benzoylbenzoic acid groups; 1.25 g/Lpolyacrylamide; 2.5 g/L PVP (K90); and 0.05 g/L photo-crosslinker; in asolvent solution of 85:15 water/isopropanol. Crosslinkers were preparedas described in US Patent Application Publication 2012/0046384,Kurdyumov et al. After coating, the basecoat material was dried at roomtemperature for 15 minutes and then irradiated with UV light for 3minutes.

Example 7 Paclitaxel (PTX) Adsorption from Suspensions—Comparison withPolymers with Pendent Primary Amines

Half of the number of wells (columns 7-12) in Matrigel® coated 96-wellplates (BD Biosciences) were seeded with human coronary arteryendothelial cells (HCAEC)-(200 μL of 10⁵ cells/mL) and incubated at 37°C. for 24 hours.

Suspensions of 11 mg/mL paclitaxel crystals (prepared as described inpatent '485 with sonication) in water with dissolved polymers at 1 mg/ml(92:8 ratio PTX/PEI), were prepared.

The following polymers were used:

TABLE 6 Example Polymer CEx 1 Branched poly(ethyleneimine) (PEI; 750kDa; available from Polysciences) CEx 2 Branched poly(ethyleneimine)(PEI; 70 kDa; available from Polysciences) Ex 1 Poly(allylamine) (PAA;25 kDa; available from Polysciences, Warrington, PA) Ex 2 100% pNVF(poly(N-vinylformamide; Polymer A above) Ex 3 50%poly(N-vinylformamide); (Polymer A50 above) Ex 4 100% pNVA (Polymer A100above; hydrolyzed poly(N-vinylformamide) Ex 5 PVP-co-pNVA 50:50 molfraction ratio

Each of the formulations (5 μL) in Table 6 above was pipetted in the 100μL medium of 8 wells without cells and 8 wells with HCAEC (HumanCoronary Artery Endothelial Cells; available from Lonza, Cologne,Germany) in the Matrigel™ (available from Becton, Dickinson and Company,Franklin Lakes, N.J.) coated well-plate and left for 3 minutes.Immediately upon completion of exposure time the wells were rinsed 3times with 200 μL PBS. Adsorbed PTX was dissolved in MeOH/0.1% aceticacid (AcOH) and quantified by HPLC (see FIG. 12).

As noted above, various water-soluble poly-amines have been synthesizedbased on copolymerizing or polymerizing N-vinyl formamide (pNVF) andsubsequent hydrolysis of the N-formamide group to obtain poly(N-vinylamine) (pNVA) groups.

Example 8 Paclitaxel (PTX) Adsorption from Suspensions—Copolymers of PVPand Poly(N-Vinyl Amine): Polymers with Pendent Primary Amines

Matrigel® coated 96-well plates (BD Biosciences) were used withoutseeding any cells on the surface. 100 μL cell medium was pipetted in thewells and the plate was warmed to 37° C. Suspensions of 11 mg/mLpaclitaxel crystals (prepared as described in patent 485 withsonication) in water with dissolved polymers at 1 mg/ml (92:8 w/w ratiopaclitaxel vs polymer) were prepared.

The following polymers were used:

-   -   a. PVP-co-pNVA 20:80 mol fraction ratio    -   b. PVP-co-pNVA 40:60 mol fraction ratio    -   c. PVP-co-pNVA 50:50 mol fraction ratio    -   d. PVP-co-pNVA 60:40 mol fraction ratio    -   e. PVP-co-pNVA 80:20 mol fraction ratio    -   f. 100% PVP (K90, BASF)    -   g. 100% pNVA.

Per formulation 5 μL was pipetted in the 100 μL medium in 6 wells. Uponaddition the plate was left for 3 minutes for the suspensions to settle.Immediately upon completion of exposure time the wells were rinsed 3times with 200 μL PBS. Adsorbed PTX was dissolved in MeOH/0.1% v/v AcOHand quantified by HPLC Z-potential of the formulations were acquiredusing DLS (Malvern Zetasizer). All mixtures were diluted in DI water500×.

A linear correlation between the wt % of the pNVA fraction versusadhered paclitaxel was found (r²=0.98) (see FIG. 13). A similar linearcorrelation was found between the wt % of the pNVA fraction versus theZeta-potential of paclitaxel crystals (see FIG. 14).

Example 9 Ex-Vivo Testing with Rapamycin

In the experiments balloon stubbies (20 mm) were used that were coatedas described above. Rapamycin (available from LC-Laboratories) wasdissolved in acetone at 200 mg/mL. Twice one mL of the solution waspipetted quickly into 20 mL DI water while stirring. The mixture wasleft stirring for 30 minutes at room temp to allow the majority ofacetone to evaporate. The mixture was then freeze-dried overnight.

The following coating solutions were prepared:

-   -   a) Rapamycin solids at 50 mg/mL in water with 10 mg/mL PEI 750        kDa at pH 7    -   b) Rapamycin solids at 50 mg/mL in water with 10 mg/mL        poly(N-vinyl amine)    -   c) Rapamycin solids at 50 mg/mL in water with 10 mg/mL 50/50        poly(PVP-co-N-vinyl amine)    -   d) Rapamycin solids at 50 mg/mL in water (no excipient)

HT-coated balloons received 14 μL of top-coat aiming for 700 μg (˜3μg/mm²). The stubbies were dried overnight, pleated and folded and‘baked’ for 1 hour at 50° C. and tested in excised arteries. PBS wasused for the soaking of the stubbies for 30 seconds prior to expansionin arteries. PBS was used as medium for the arteries for subsequentinflation and rinsing. The results are shown in FIG. 15.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

It should also be noted that, as used in this specification and theappended claims, the phrase “configured” describes a system, apparatus,or other structure that is constructed or configured to perform aparticular task or adopt a particular configuration to. The phrase“configured” can be used interchangeably with other similar phrases suchas arranged and configured, constructed and arranged, constructed,manufactured and arranged, and the like.

In the Specification and claims, the term “about” is used to modify, forexample, the quantity of an ingredient in a composition, concentration,volume, process temperature, process time, yield, flow rate, pressure,and like values, and ranges thereof, employed in describing theembodiments of the disclosure. The term “about” refers to variation inthe numerical quantity that can occur, for example, through typicalmeasuring and handling procedures used for making compounds,compositions, concentrates or use formulations; through inadvertenterror in these procedures; through differences in the manufacture,source, or purity of starting materials or ingredients used to carry outthe methods, and like proximate considerations. The term “about” alsoencompasses amounts that differ due to aging of a formulation with aparticular initial concentration or mixture, and amounts that differ dueto mixing or processing a formulation with a particular initialconcentration or mixture. Where modified by the term “about” the claimsappended hereto include equivalents to these quantities.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference. To the extent inconsistencies arise betweenpublications and patent applications incorporated by reference and thepresent disclosure, information in the present disclosure will govern.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A drug delivery device comprising: a substrate;an uncharged hydrophilic polymer layer disposed on the substrate, theuncharged hydrophilic polymer layer comprising a biostable synthetichydrophilic polymer comprising one or more of acrylic monomers, vinylmonomers, and ether monomers; and a coated therapeutic agent particlelayer disposed on the uncharged hydrophilic polymer layer, the coatedtherapeutic agent particle layer consisting of coated therapeutic agentparticles comprising: a particulate hydrophobic therapeutic agent; andPVP-co-pNVA at a mol fraction of 20:80 PVP:pNVA to 80:20 PVP:pNVA; andwherein the coated therapeutic agent particle layer is configured as anoutermost layer of the drug delivery device for direct contact with anin vivo environment.
 2. The drug delivery device of claim 1, the coatedtherapeutic agent particles exhibiting a Zeta potential of greater than+10 mV.
 3. The drug delivery device of claim 1, the particulatehydrophobic therapeutic agent having an average diameter of between 100nm and 10 μm.
 4. The drug delivery device of claim 1, the particulatehydrophobic therapeutic agent having an average diameter of between 0.3μm to about 1 μm.
 5. The drug delivery device of claim 1, theparticulate hydrophobic therapeutic agent selected from the groupconsisting of paclitaxel, sirolimus, and analogs thereof.
 6. The drugdelivery device of claim 1, the uncharged hydrophilic polymer layercovalently bonded to the substrate.
 7. The drug delivery device of claim1, the uncharged hydrophilic polymer layer cross-linked with aphotoactivatable cross-linking agent.
 8. The drug delivery device ofclaim 1, the device comprising a drug-containing balloon catheter.
 9. Adrug delivery coating comprising a polymeric layer, the polymeric layercomprising an uncharged hydrophilic surface configured to be disposed ona substrate, the uncharged hydrophilic polymer layer comprising abiostable synthetic hydrophilic polymer comprising one or more ofacrylic monomers, vinyl monomers, and ether monomers; a coatedtherapeutic agent particle layer disposed on the hydrophilic surface,the coated therapeutic agent particle layer consisting of coatedtherapeutic agent particles comprising: a particulate hydrophobictherapeutic agent core; and PVP-co-pNVA at a mol fraction of 20:80PVP:pNVA to 80:20 PVP:pNVA; and wherein the coated therapeutic agentparticle layer is configured as an outermost layer of the drug deliverydevice for direct contact with an in vivo environment.
 10. A medicaldevice comprising: a capsule housing; control circuitry disposed with inthe capsule housing; at least one moveable element operably connected tothe capsule housing, the moveable element comprising a substrate and acoating disposed on the substrate, the coating comprising; an unchargedhydrophilic polymer layer disposed on the substrate, the unchargedhydrophilic polymer layer comprising a biostable synthetic hydrophilicpolymer comprising one or more of acrylic monomers, vinyl monomers, andether monomers; and a coated therapeutic agent particle layer disposedon the hydrophilic polymer layer, the coated therapeutic agent particlelayer consisting of coated therapeutic agent particles comprising: aparticulate hydrophobic therapeutic agent; and PVP-co-pNVA at a molfraction of 20:80 PVP:pNVA to 80:20 PVP:pNVA; and wherein the coatedtherapeutic agent particle layer is configured as an outermost layer ofthe drug delivery device for direct contact with an in vivo environment.11. The medical device of claim 10, the control circuitry configured tocause the moveable element to move between a deployed position and anon-deployed position; the medical device comprising a total width,wherein the total width of the medical device is greater in the deployedconfiguration than in the non-deployed configuration.
 12. The drugdelivery device of claim 1, further comprising PVP-co-pNVA at a molfraction of 40:60 PVP:pNVA to 60:40 PVP:pNVA.
 13. The drug deliverydevice of claim 1, further comprising PVP-co-pNVA at a mol fraction of50:50 PVP:pNVA.